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Our Projects

The long-term goal of the LA CaTS Pilot Grants Program is to develop a critical mass of senior scientists and promising young investigators trained in translational research. Below are the projects and investigators supported through the LA CaTS Center Pilot Grants Program and other LA CaTS Center Cores or Resources.


Annual Pilot Grant Awards




Special or Theme Focused Pilot Grant Awards



Round 1 Pilot Projects

Metabolic Effects of Short Term Sugarcane Bagasse Supplementation
Daniel Hsia, Pennington Biomedical Research Center

Diets high in fiber have been shown to reduce the risk of type 2 diabetes and cardiovascular disease.  However, the average American diet contains ~10 to 15 g of fiber per day and is well below the 20-35 g of fiber per day recommended by the Academy of Nutrition and Dietetics (formerly the American Dietetic Association).  Therefore, there is a need to study methods of increasing dietary fiber intake as well as novel sources of dietary fiber.  Sugarcane bagasse is the remaining fibrous material after sugarcane juice is extracted.  Pre-clinical studies have shown attenuated weight gain, enhanced insulin sensitivity via HOMA-IR, lower ghrelin gene expression, and increased GLP-1 levels in mice fed a high fat diet plus sugarcane fiber compared to mice fed the same diet plus cellulose fiber.  This 4 week double-blind placebo-controlled pilot study in obese, insulin-resistant adults aims to translate these results into humans.  We hypothesize that subjects who consume food supplemented with sugarcane bagasse will have improved glucose tolerance and insulin sensitivity (via OGTT), less weight gain, increased satiety, higher GLP-1 levels, and lower ghrelin levels.

Evaluation of ACE2 as a Biomarker for Neurogenic Hypertension
Eric Lazartigues, LSU Health Sciences Center New Orleans

ACE2 activity is reduced in the central nervous system (CNS) during the development of experimental neurogenic hypertension. This could result from the enzyme being cleaved from the cell membrane through "shedding" by ADAM 17, also known as TNFα convertase. This "shedding" of ACE2 could lead to increased levels of soluble ACE2 within the CNS which is thought to be associated with hypertension and other cardiovascular diseases. Therefore, measurement of soluble ACE2 in the CNS could be used as a biomarker for developing neurogenic hypertension. We assessed ADAM 17 activity in the brain by measuring soluble ACE2 and TNFα in the cerebro‐spinal fluid of patients by ELISA and mass spectrometry. CSF samples were obtained from 30 patients divided in 3 groups: normotensive (n=15), hypertensive (n=4), and hypertensive controlled with medication (n=11). While Elisa lacked sensitivity, soluble levels of hACE2 could easily be detected by RAS‐Fingerprint™ in all patients. Increased ACE2 activity in the CSF was associated with hypertension. On the other hand, patients taking antihypertensive medications appear to show normalization of ACE2 levels in the CSF. In conclusion, soluble ACE2 activity in the CSF is correlated with high blood pressure and could be used as a biomarker of neurogenic hypertension.

Transcriptional Profiling of Gastritis Progression Using High Throughput Sequencing of Tissue MicroRNA
Jovanny Zabaleta, LSU Health Sciences Center New Orleans

Gastric cancer is one of the most common of all cancers and has one of the highest prevalence and mortality rates worldwide. More than 20,000 new cases of gastric cancer are expected in 2013, and more than 10,000 deaths will be attributed to the disease. Among all the risk factors, which include diet, age and ethnicity, infection with Helicobacter pylori (H. pylori) is the only irrefutable factor associated with the disease, especially in the intestinal form of gastric cancer. Because of this relationship, H. pylori is classified as a Type I carcinogen by the International Agency for Research in Cancer (IARC). A chronic inflammatory cascade from normal epithelia to non-atrophic gastritis (NAG), to multifocal atrophic gastritis (MAG), to intestinal metaplasia, dysplasia and cancer is initiated by the infection and can persist even after the eradication of H. pylori. Thus, determining the ideal therapeutic approach to delay or prevent the progression of inflammatory lesions to gastric cancer remains challenging. We have shown that single nucleotide polymorphisms (SNP) in cytokine genes are differentially associated with risk of advanced gastric lesions in African American and Caucasian individuals.  However interesting, these are cross-sectional results and, thus, we are not able to explore gene profiles associated with the evolution of these gastric lesions. microRNA (miRNA) are small 18 - 24 nucleotide molecules known to interfere with both translation and transcription. Several profiles of miRNA have been associated with cancer risk but their role in disease evolution is still unknown. In this application we propose the innovative use of sequential biopsies from individuals with differential outcomes to evaluate the inflammatory lesion-to-malignancy cascade using high throughput sequencing. Our goal is to compare miRNA profiles in gastric biopsies at baseline and 12 years later to determine if there are specific gene sets, which can be associated with progression or regression of the disease.

Using Serum microRNAs as Biomarkers for Cognitive Impairment in HIV Patients
Francesca Peruzzi, LSU Health Sciences Center New Orleans

Human Immunodeficiency Virus (HIV)-infected individuals are at increased risk for developing depression and other neurocognitive disorders, but neurobiological mechanisms underlying mental deterioration in HIV-positive individuals remain unknown. Neurocognitive impairment and depression adversely impact HIV treatment adherence. Thus, identification of early markers of neurocognitive impairment could lead to interventions that improve psychosocial functioning and slow disease progression through improved treatment adherence.
MicroRNAs are short non-coding RNAs that regulate gene expression. microRNAs are key regulators of synaptic plasticity and brain development and, as such, could contribute to the etiopathology of neurocognitive disorders. In addition, microRNAs secreted into body fluids can serve as diagnostic and/or prognostic markers for a variety of diseases. Here, we present preliminary results of differentially regulated plasma microRNAs from 21 HIV-1 positive patients grouped on the basis of their neurocognitive status and/or symptoms of depression.  Results indicate that plasma miRNAs may serve as useful biomarkers for HIV-associated neurocognitive disorders.

MicroRNAs as Prognostic Markers of Breast Cancer
Suresh Alahari, LSU Health Sciences Center New Orleans

Our hypothesis is that miR-27b and miR-23b function as oncogenes by suppressing the function of Nischarin and ST14 tumor suppressors (and possibly other unknown proteins as well), and thus miR-27b and miR-23b are key regulators and good prognostic markers of breast tumor growth and metastasis. We believe these microRNAs have similar prognostic importance as Her2/Neu in breast cancer.  We will test our hypothesis by examining the prognostic importance of miR-27b and miR-23b in breast cancer patients. Here we will examine the expression levels of these two microRNAs in sera of breast cancer patients and controls. It is known that serum microRNAs can be diagnostic and/or prognostic markers for breast cancer. Moreover, blood sampling is minimally invasive and easy to obtain, and thus it is attractive to explore for potential biomarkers in blood.  We will screen blood serum of 103 cancer patients and 103 controls, and this would reveal the prognostic role of these microRNAs in breast cancer.

Discovering the Role of Putative MicroRNAs in Prostate Tumorigenesis
Zakaria Abd-Elmageed, Tulane University

Prostate cancer (PC) is the most frequent cancer among older men. PSA is the most common diagnostic biomarker; however it has well known limitations. Microvesicles (MVs) are cell-derived extracellular bodies, which promote cell-cell communications. The identification of tissue- or disease-specific MVs miRNAs will enable the use of these vesicles as a source of new biomarkers. Our aim is to investigate the differential expression of selected putative onco-miRNAs in normal and PC cells and further establish their clinical utilities as biomarkers for PC. Here, we report the potential role of MVs-associated miRNAs in PC progression and their utility as biomarkers in vitro and in human tissues. The expression of onco-miRNAs was higher in PC patients than normal subjects. High expression of miRNAs suppressed their related targets of tumor suppressor genes, and ectopic expression of some of these onco-miRNAs in benign PC cell lines increased cell growth, migration and invasion.

Urinary Excretion of Renin and Soluble Prorenin Receptor in Hypertension
Minolfa Prieto, Tulane University

The prorenin receptor (PRR) increases renin activity and activates prorenin. To test the hypothesis that increased levels of soluble PRR (sPRR) enhances renin activity in the kidneys of hypertensive (HTN) patients, we measured the urine levels of free sPRR and renin activity (uRen) from 56 patients, including normal subjects (CT; n=18) and patients with HTN without (n=18) and with concurrent diabetes mellitus (DM; n=20). Twenty-six (48%) were women (51±13 years-old) and 30 (51%) were men (50±16 years-old). s(P)RR levels did not differ between HTN and HTN+DM patients but were lower compared to CT (HTN: 580±131 and HTN+DM: 500±85 vs. CT: 1,248±346 pg/mg; p<0.05). uRen activity was similar between HTN and CT subjects (22±9 vs. 25±10 ngAngI/hr/mL), but higher in HTN+DM patients (164±16 ngAngI/ml/hr; p<0.05). These data suggest that PRR bound to cell membrane, but no sPRR, might be responsible for the increases in uRen activity in HTN patients with DM.

Time Restricted Feeding to Improve Insulin Sensitivity and Vascular Function
Courtney Peterson, Pennington Biomedical Research Center

It is widely believed that grazing improves blood sugar control and overall health. However, recent evidence in rodents suggests that grazing contributes to weight gain, inflammation, and worse glucose tolerance. In comparison, time-restricted feeding (TRF), which involves eating in a narrow time window followed by a daily 15-20 hour fast, reduced metabolic disease and abrogated weight gain in rodents.  We will conduct the first pilot study of TRF in humans.  In this crossover study, 8 obese men will be randomized to either 5 weeks of TRF or grazing, followed by a 7-week washout period, and then 5 weeks of the other feeding condition.  Calories, meal frequency, and diet composition will be matched in each group. Before and after each arm of the study, glucose homeostasis, vascular function, inflammation, and key hormones will be measured. It is hoped that this study will lead to novel insights into how meal timing impacts health and disease risk.

Predicting the Response of Lipoproteins to Exercise using Clinical and Genetic Data
Mark Sarzynski, Pennington Biomedical Research Center

There is large inter-individual variation in the magnitude of changes in plasma lipoprotein traits derived from regular exercise, and genetic factors appear to contribute to this variability. However, the associations of genomic markers with exercise-induced changes in lipoprotein particle traits have not been thoroughly explored. We hypothesize that adding information on genomic markers will significantly improve our ability to predict the responsiveness of lipoprotein particle traits to regular exercise above and beyond the commonly used clinical predictors. We will test this in the following aims:

Aim 1: Examine the response of lipoprotein particle traits to regular exercise in four exercise training studies in order to define significant clinical predictors of response.

Aim 2: Test whether genetic summary scores derived from GWAS improve the prediction of the response of lipoprotein particle traits to regular exercise compared to standard clinical assessment variables, and determine if this enhanced prediction level is clinically meaningful.

Round 2 Pilot Projects

Assessing and Reducing Risk of Violence and Violent Injury Among Victims of Urban Violence
Erich Conrad, LSU Health Sciences Center New Orleans

Victims of urban violence face a perilous trek even after their physical injuries heal. For victims,violent trauma is a recurrent event and many later even die from violence. Victims of urban violence often have histories of violence perpetration and are at a heightened risk for violence in the wake of traumatic injury. Multiple, interrelated risk factors predict later violence and violent injury. Risk behaviors are often exacerbated following traumatic injury, potentially leading to a self-perpetuating cycle of violence and victimization. Interventions to promote behavioral changes that reduce risk may thus be critical in preventing further violence and violent injury. The hospitalization immediately following violent trauma may be a unique window for such care, yet few hospital-based programs exist and empirical evaluations of these programs have yielded mixed results. Our lab has developed an initial draft protocol of a hospital-based intervention for victims of urban violence that is rooted in Transtheoretical Model of Change and Motivational Interviewing.

We propose to refine, implement, and pilot test this intervention among patients hospitalized following a violent injury at an urban Level I Trauma Center. The proposed study will be conducted in two phases: (Year 1) a pre-randomized development phase to systematically refine and standardize our intervention and (2) a pilot randomized clinical trial of efficacy. The RCT will randomly assign violently injured patients to (a) treatment as usual (brief mental health screening and referral (n = 50); (b) a hospital-based Ml protocol (n = 50). Phase 1 outcome measures include both quantitative and qualitative assessments of acceptability and feasibility Phase II primary proximal outcome variables are motivation to change and actions taken to mitigate risk. Phase II distal outcome variables are violent behavior, arrests for violence crime, violent injury, and hospital service utilization due to violent trauma. Risk behaviors (substance abuse, weapon use, anger/irritability, belief in the utility of violence, post-traumatic stress symptoms, unemployment, lack of education, and unstable housing) are included as medial outcomes to examine possible mechanisms of influence between proximal and distal outcome variables.

Investigation of novel genetic factors predisposing to multiple epiphyseal dysplasia and osteoarthritis
Malwina Czarny-Ratajczak, Tulane University

Multiple epiphyseal dysplasia (MED) is a relatively common chondrodysplasia characterized by delayed and irregular ossification of epiphyses and early-onset osteoarthritis (OA). This clinically and genetically highly heterogeneous disorder is caused by mutations in six genes. However, mutations in these genes only explain approximately 50% of all cases, which indicates that defects in other genes are involved. Currently, the overlapping MED/OA phenotype is being reinvestigated since it may provide new insights towards understanding the genetic basis for common forms of osteoarthritis. Our central hypothesis is that there are new candidate genes for MED and mutations in these genes may also contribute to the development of common forms of OA. We plan to identify a new gene(s) for MED using exome-sequencing in four families for whom we have previously excluded all currently known candidate genes and identified a high lod score (5.45) on chromosome 11 indicating a new locus for this disease. We will then determine if changes in the new MED candidate gene predispose to primary OA, by sequencing of the new candidate gene in Louisiana patients with primary knee OA. With respect to expected outcomes, this project has a high chance to result in discovery of a new gene that mutations cause MED and OA. Identification of this gene may also help to develop a new treatment for these disorders; however, this strongly depends on the function of a coded protein. We are planning to analyze this gene in patients with OA from Louisiana and to estimate the genetic predisposition in this group in collaboration with Dr. Vinod Dasa of LSU.

HPV and EBV Serum Antibodies as Prognostic Markers for Cervical Cancer
Rebecca Fisher, LSU Health Sciences Center New Orleans

Human papilloma virus (HPV) is necessary but not sufficient for development of cervical cancer, an epithelial cell malignancy. We have evidence supporting Epstein-Barr Virus (EBV) as a co-factor for HPV related cervical disease in HIV+ women. EBV is the causative agent of the epithelial cell malignancy nasopharyngeal carcinoma (NPC). Serum antibodies against EBV antigens are the best predictor of NPC in high risk populations. This proposal will assess whether serological assays for HPV and EBV antibodies can serve as prognostic indicators of cervical disease. HIV+ human serum samples will be evaluated for 5 antibody markers against EBV and 6 antibody markers against HPV. This data will be combined with my preliminary data to determine the best combination of serum antibodies for predicting cervical disease. The advantages of serum testing will likely increase patient compliance for screening and follow up of cervical disease and therefore improve outcomes for cancer patients.

Evaluation of peg-Arginase I as a Therapeutic for Virus-Mediated Ocular Diseases
Timothy Foster, LSU
Health Sciences Center New Orleans

Pathogen-associated ocular diseases are a complex combination of pathogen-mediated trauma and hostmediated inflammation-associated pathologies. We have developed an ophthalmic formulation of pegylated-ArginaseI(peg-ArgI) that has broad anti-pathogen, anti-inflammatory, and antineovascularization activities, while also promoting healing of traumatic corneal wounds (Patents:US13/828,669;PCT/US13/31623). No current drug has all these combined activities. Targeting host metabolic pathways by peg-ArgI to simultaneously ameliorate pathogen- and host-mediated disease sequelae is a novel therapeutic approach with wide-ranging clinical potential. The rabbit eye is an FDA recognized model for establishing an ophthalmic drug's pharmacological parameters and evaluating clinical efficacy prior to initiating human trials. We will utilize this model to: 1) Establish a dosing regimen for peg-ArgI that prevents both HSV-1 replication and presentation of ocular pathologies and 2)Evaluate peg-ArgI's ocular safety and toxicity according to FDA recognized protocols. Establishment of these pre-requisite parameters will provide critical support for future human trials of peg-ArgI as a broadly applicable ophthalmic therapeutic.

Analysis of the Pathogenesis of HIV/EBV associated DLBCL
Zhen Lin, Tulane University

Currently, the state of Louisiana has the 4th highest annual AIDS diagnosis rate and the 10th highest HIV/AIDS population in the United States. Nearly 70% of AIDS patients in Louisiana are African American (Kaiser family foundation / HIV/AIDS is considered one of the major health problems in Louisiana, especially in the medically underserved population. AIDS associated malignancies such as Diffuse Large B-cell lymphomas (DLBCLs) are one of the major factors for AIDS-related morbidity and mortality. The objective of this project is to determine the precise role of Epstein-Barr virus (EBV) in the pathogenesis of the AIDS/EBV associated DLBCLs using the most clinically relevant model system available - clinical specimens. EBV is a primary driver of AIDS associated DLBCLs with a penetrance of nearly 100%. We will use expression and genetic signatures of clinical lymphoma biopsies to determine EBV signaling mechanisms driving lymphomagenesis in AIDS patients.

Targeted microRNA analysis in Multiple Sclerosis associated cognitive decline
Jesus Lovera, LSU Health Sciences Center New Orleans

Deidre Devier, LSU Health Sciences Center New Orleans

Two-hundred-thousand Americans with Multiple Sclerosis (MS) will develop cognitive impairment (CI) resulting in unemployment and social isolation. Innate immunity plays a key role in widespread injury to the brain underlying CI in MS. Currently we cannot measure innate immunity activation in the brain non-invasively and no treatments are available to arrest it. MicroRNAs (miRs) are small RNA molecules that regulate genes in their cell of origin and surrounding cells. MiRs regulating innate immunity activation or linking it with neurodegeneration are over-expressed in CSF of people with Alzheimer disease. Our hypothesis is that these same miRs play an important role in CI in MS; to test our hypothesis we will compare CSF miR in people with MS with and without CI and correlate CSF miRNA with MRI measures of tissue injury. This is a first step in testing this hypothesis, opening novel diagnostic and treatment possibilities for CI in MS.

Development of a PACAP Analog as a Therapeutic for Contrast-Induced Nephropathy
Jerome Maderdrut, Tulane University

The incidence of contrast-induced nephropathy in the general population is low, but can exceed 50% in some subpopulations. No drugs have been approved by the FDA specifically for the prevention of contrast-induced nephropathy. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a multifunctional peptide with potent anti-inflammatory and cytoprotective properties. We have shown that PACAP is efficacious in a novel model of contrast-induced nephropathy. We have synthesized and characterized two series of proprietary PACAP analogs. We have submitted a proposal to NIH to acquire the funds needed to move a lead compound from the preclinical stage of development past the Investigational New Drug application stage of development. The proposal was scored but not funded. There were three major criticisms. The receptor binding data has now been determined by our collaborators. The purpose of this proposal is to obviate the other two major criticisms and then resubmit the scored NIH proposal.

Screening for glycosylation disorders and study galactose intake in PGM1-CDG
Eva Morava-Kozicz, Tulane University

Hypoglycemia is the most common metabolic condition in newborns and infants. We defined a novel inborn error of metabolism due to Phosphoglucomutase (PGM1) deficiency. The novel condition presents with severe neonatal, and recurrent infantile hypoglycemia associated with abnormal growth and endocrine abnormalities of variable degree (Mohamed et al, BBA, 2011, Timal et al., HMG, 2012). Since 2012 more than 20 patients have been diagnosed with this condition. PGM1 deficiency leads to progressive increase of glycogen concentration in muscle and liver and abnormal protein glycosylation (Congenital disorder of glycoslation: CDG) in blood. In an adolescent patient we observed variable disease severity, depending on the daily milk intake (galactose intake), over a one-year period. One year of therapy with extra oral galactose intake resulted in improved N-linked glycosylation, normalization of liver function tests, prevention of hypoglycemic episodes, and normalization of N-glycosylated hormones and IGF1/IGF3. These observations led us to the hypothesis that PGM1 deficiency alters the balance of glucose-1- and galactose-1-phosphate concentrations leading to abnormal N-glycosylation, and that this phenomenon is most likely influenced by dietary galactose availability.

Aims of our study:

  1. Hypoglycemia is a common symptom of the Congenital Disorders of Glycosylation (CDG). None of the types of the CDGs have been screened in Louisiana, and no metabolic diagnostic test is available in our state for the more than 50 different types of this condition. We will start a collaborative effort with LSU Health Sciences Center and Children's Hospital, to set up selective CDG screening, using10 ul plasma or dried Blood spot on filter paper, by transferrin isoelectric focusing (TIEF) in hypoglycemic newborns and infants.
  2. We clinically follow five patients with the recently discovered inborn error; PGM1 deficiency. The patients are of different age and have a natural, variable galactose intake and remain under regular metabolic and dietary control. In order to study the effects of oral galactose intake on the clinical and biochemical features of affected patients, we will evaluate the correlation between galactose intake, growth parameters, clinical symptoms, diet, and follow the N-glycosylation pattern by TIEF and glucose regulaton related endocrine parameters. These evaluations will be performed on a monthly basis over a one-year period.

Background: The principle investigator has been active as a clinician and scientist in Europe and joined the faculty at Tulane University in 2012. She is a clinical and biochemical geneticist. She has significant expertise in congenital disorders of glycosylation including the description of the PGM1-related glycosylation defect and other new gene discoveries. Deliverables: This study will allow (1) establishment of a novel research line on protein glycosylation at the Hayward Genetics Center (2) collaboration between the Departments of Pediatrics and Genetics at Tulane University and LSUHSC (3) initiation of selective screening for protein glycosylation defects in Louisiana, (4) development of more pathophysiological insight of a novel metabolic disease.

Boron-based 4-hydroxytamoxifen and endoxifen prodrugs for treatment of breast cancer
Guangdi Wang, Xavier

Poor initial response to tamoxifen therapy and persistent side effects remain major clinical challenges in the treatment of breast cancer patients. The boron-based 4-hydroxytamoxifen and endoxifen prodrugs are designed to address both problems by guaranteed delivery of a more potent metabolite of tamoxifen without requiring a functional enzyme (CYP2D6) to convert tamoxifen to 4-hydroxytamoxifen and endoxifen, and by lowering the dose requirement to reduce side effects such as hot flash. The proposed animal study is expected to confirm that the superior activities of the prodrugs in breast cancer cells can be extended to in vivo models. These results will lay the ground work for more extensive pre-clinical studies leading to clinical trials.

Plaque Destabilization through Shear Stress Mediated Decreases in miR-221/222
T. Cooper Woods, Tulane University

Our limited understanding of the mechanisms behind plaque rupture is a critical barrier to developing methodologies for prevention of myocardial infarction and stroke. Our lab has found the expression of two microRNAs and a related circular RNA are altered in plaques postrupture and in relation to shear stress. We hypothesize that increased shear stress alters noncoding RNA (ncRNA) expression to promote plaque destabilization. We will test this via two aims. Aim 1 will identify ncRNAs associated with plaque rupture using next generation sequencing and relate their expression to shear stress. Aim 2 will use a custom-designed bioreactor to demonstrate in vitro that increases in laminar shear stress reduce proliferation and increase apoptosis in vascular smooth muscle cells through changes in ncRNA expression. This project thus combines an innovative approach to studying plaque rupture with cutting edge methodology to determine the role of flow mediated changes in ncRNA in plaque destabilization.

Selective targeting of the metastatic-invasive phenotype of triple-negative breast carcinoma
Bridgette Collins-Burrow, Tulane University

Introduction: Of the more than one million global cases of breast cancer diagnosed each year, approximately fifteen percent are characterized as triple-negative, lacking the estrogen, progesterone, and Her2/neu receptors. Lack of effective therapies, younger age at onset, and early metastatic spread have contributed to the poor prognoses and outcomes associated with these malignancies. Here, we investigate the ability of the histone deacetylase inhibitor panobinostat (LBH589) to selectively target triple-negative breast cancer (TNBC) cell proliferation and survival in vitro and tumorigenesis in vivo.

Methods: TNBC cell lines MDA-MB-157, MDA-MB-231, MDA-MB-468, and BT-549 were treated with nanomolar (nM) quantities of panobinostat. Relevant histone acetylation was verified by flow cytometry and immunofluorescent imaging. Assays for trypan blue viability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) proliferation, and DNA fragmentation were used to evaluate overall cellular toxicity. Changes in cell cycle progression were assessed with propidium iodide flow cytometry. Additionally, qPCR arrays were used to probe MDA-MB-231 cells for panobinostat-induced changes in cancer biomarkers and signaling pathways. Orthotopic MDA-MB-231 and BT-549 mouse xenograft models were used to assess the effects of panobinostat on tumorigenesis. Lastly, flow cytometry, ELISA, and immunohistochemical staining were applied to detect changes in cadherin-1, E-cadherin (CDH1) protein expression and the results paired with confocal microscopy in order to examine changes in cell morphology.

Results: Panobinostat treatment increased histone acetylation, decreased cell proliferation and survival, and blocked cell cycle progression at G2/M with a concurrent decrease in S phase in all TNBC cell lines. Treatment also resulted in apoptosis induction at 24 hours in all lines except the MDA-MB-468 cell line. MDA-MB-231 and BT-549 tumor formation was significantly inhibited by panobinostat (10 mg/kg/day) in mice. Additionally, panobinostat upregulated CDH1 protein in vitro and in vivo and induced cell morphology changes in MDA-MB-231 cells consistent with reversal of the mesenchymal phenotype.

Conclusions: This study revealed that panobinostat is overtly toxic to TNBC cells in vitro and decreases tumorigenesis in vivo. Additionally, treatment up-regulated anti-proliferative, tumor suppressor, and epithelial marker genes in MDA-MB-231 cells and initiated a partial reversal of the epithelial-to-mesenchymal transition. Our results demonstrate a potential therapeutic role of panobinostat in targeting aggressive triple-negative breast cancer cell types.

Keywords: Panobinostat, LBH589, triple-negative breast cancer, xenograft, histone deacetylase inhibitor, E-cadherin, CDH1, epithelial-to-mesenchymal transition

Round 3 Pilot Projects

Molecular Epidemiology and Natural History of Acadian Usher syndrome
Jennifer Lentz, LSU Health Sciences Center New Orleans

Usher syndrome (Usher), the most frequent genetic cause of deaf-blindness, affects 1 in 20,000 individuals worldwide, but is more frequent in some close-knit communities. Fifteen genes are associated with three clinical subtypes. The USH1C c.216G>A mutation accounts for nearly all USH1 cases in the Acadian population of Louisiana. Due to founder effect, the frequency of USH1C appears to be higher in Louisiana, however the real incidence and natural history among our patients is unknown. We created a knock-in mouse containing the Acadian c.216G>A mutation, and showed that treatment with antisense oligonucleotides prevents hearing impairment and improves vision when given early in life. Moving this unique therapeutic opportunity into the clinic requires a better understanding of the incidence in Louisiana, and a clear picture of its clinical evlolution. Our goals are to conduct molecular epidemiology studies and develop a clinical natural history of USH1C in Louisiana, necessary for planning clinical trials.

Cardiovascular disease inflammation is due to macrophage associated lipin-1 activity
Matthew Woolard, LSU Health Sciences Center Shreveport

Cardiovascular disease (CVD) is the number one killer of Louisiana residents, thus new therapeutic options are needed. The underlying cause for almost all catastrophic CVD events is atherosclerosis. Atherosclerosis is a macrophage-mediated chronic inflammatory disorder, thus, inhibition of this inflammation is a potential therapeutic approach to treat CVD. To develop anti-inflammatory therapeutic strategies to treat CVD without making the individual immuno-suppressed we must identify processes that are unique to atherosclerosis.  Our work has identified a lipid synthetic enzyme, lipin-1, that uniquely contributes to atherosclerotic macrophage inflammatory responses. Our results suggest this is a targetable process (lipid synthesis by macrophages) that initiates atherosclerotic inflammation. This proposal will elucidate the mechanism by which lipin-1 elicits atherosclerotic inflammation in vitro and test the feasibility of targeting this protein to treat CVD in vivo. As such this proposal is a vital translational step in the development of new therapies to treat individuals with CVD.

Vaccine efficacy in diabetic and elderly patients
Elizabeth Norton, Tulane University

Our goal is to determine if an individual's level of inflammation determines their response to vaccination. The aging process and certain diseases, like type-2 diabetes, have been characterized as chronic inflammatory conditions. Affected individuals have higher rates of influenza disease and health care costs; hence, yearly vaccination is recommended. There is a paucity of information comparing vaccination in these high-risk groups and identifying biomarkers that can predict vaccine efficacy. We hypothesize that elderly and diabetic patients have reduced responses to seasonal influenza vaccination that are inversely proportional to their level of chronic inflammation. In this pilot proposal, we will examine adult and elderly diabetic and non-diabetic adults for markers of inflammation and vaccine efficacy before and after influenza vaccination. These studies will help
our understanding of how chronic inflammatory diseases impact immunologic function and future research on mitigation strategies.

Endothelial microparticles in COPD: Effect of vascular-targeted therapy
Matthew Lammi, LSU Health Sciences Center New Orleans

An exciting avenue of drug discovery in COPD revolves around the pulmonary vasculature; changes in the pulmonary vessels/endothelium occur early in the clinical course and may play an active role in the pathogenesis of disease.  Biomarkers that may be used to facilitate new treatment strategies are endothelial microparticles (EMPs), submicron vesicles generated from endothelial cell membranes.  EMPs may be important in the pathogenesis of COPD, can be used as a biomarker indicating endothelial damage, and may be useful in determining which patients could benefit from vascular-targeted therapy.  Our current work suggests that a prostacyclin analog may selectively reduce systemic inflammation by altering the endothelium.  EMPs may be exploited to understand the mechanism of benefit of iloprost and to predict which patients will benefit from this therapy.  We propose an investigation using blood from patients with COPD receiving iloprost or placebo, as well as in vitro experiments utilizing human endothelial cells.

Testing glial pathways to HAAF in human subjects using 13C magnetic resonance spectroscopy
David McDougal, Pennington Biomedical Research Center

Hypoglycemia-associated autonomic failure (HAAF) is a condition commonly developed in diabetic patients, which often causes life threatening bouts of hypoglycemia. These hypoglycemic crises are a significant impediment to the maintenance of healthy blood glucose levels in individuals with diabetes. HAAF is thought to be driven by cellular or metabolic adaptations in the brain which alters its response to hypoglycemia. Studies in rodents have demonstrated that dietary restriction can produce alterations in brain metabolism similar to those associated with HAAF. Therefore, we hypothesize that HAAF may be driven by metabolic adaptations in the brain, normally induced by prolonged starvation, which are triggered in diabetic individuals by treatment induced exposure to hypoglycemia. The primary goal of our LA CaTS pilot project is to conduct a prospective observational study in humans to test the hypothesis that prolonged fasting will cause alterations in brain metabolism similar to those observed in individuals with HAAF.

Detection of Hereditary Colorectal Cancer Mutations in Cajuns
Jordan Karlitz, Tulane University

Cajuns are the majority of the white population in the Acadian region of south Louisiana. We have recently uncovered that colorectal cancer (CRC) prevalence in whites in the Acadian parishes are disproportionately higher than the rest of the state and are among the highest in the U.S. Furthermore, CRC is developing at a young age in the region. Since the Cajuns are a known founder population for multiple genetic diseases, it is likely that these high CRC rates are due to a founder mutation in for hereditary CRC, like Lynch syndrome (LS). In order to analyze this further, we will test CRC samples from these young Cajuns for microsatellite instability, a hallmark of LS. Our project will address an important public health concern since early intervention can effectively decrease CRC incidence and mortality.

Plaque destabilization via shear stress and vascular strain induced changes in non-coding RNA
T. Cooper Woods, Tulane University

Our limited understanding of the mechanisms behind plaque rupture is a critical barrier to developing methodologies for prevention of myocardial infarction and stroke. Our lab has found the expression of two microRNAs and a related circular RNA are altered in plaques post-rupture and in relation to shear stress. We hypothesize that increased shear stress and vascular strain alters non-coding RNA (ncRNA) expression to promote plaque destabilization. We will test this via two aims. Aim 1 will identify ncRNAs associated with plaque rupture using next generation sequencing and relate their expression to shear stress and vascular strain using computational modeling. Aim 2 will use custom-designed bioreactors to demonstrate in vitro that increases in laminar shear stress and in vascular strain reduce proliferation and increase apoptosis in vascular smooth muscle cells through changes in ncRNA expression. This project thus combines an innovative approach to studying plaque rupture with cutting edge methodology to determine the role of flow and strain mediated changes in ncRNA in plaque destabilization.

Round 4 Pilot Projects

Overcoming Immunity to Change: A feasibility study of a new method to promote medication adherence among older adults with hypertension
Marie Krousel-Wood, MD, Tulane University

The prevalence of hypertension in Louisiana exceeds the national average, with >70% prevalence among those age 65+, attributed, in part, to high prevalence of obesity across all age groups. Despite availability of lifestyle behaviors and effective medications to control blood pressure (BP), only 53% of US adults have controlled disease. Furthermore, racial and gender disparities in the control of hypertension exist. Inadequate control of hypertension is associated with poor medication adherence. Despite decades of research, no single intervention has emerged as superior in improving adherence and BP control. There is an urgent need for patient-centered interventions to improve adherence. On the basis of prior work that identified 6 ‘hidden motive' clusters associated with patients' ‘immunity to change' their medication-taking behavior, the objective of this pilot study is to assess the feasibility of using the Overcoming Immunity-to-Change approach to improve medication-taking behaviors and BP control in nonadherent elders with uncontrolled hypertension.

Effect of Combination Therapy with Sodium Nitrite and Isoquercetin on Endothelial Function and Inflammation among Patients with Chronic Kidney Disease
Jing Chen, MD, MMSc, MSc, Tulane University

Chronic kidney disease (CKD) related cardiovascular disease (CVD) and end-stage renal disease are major causes of death in Louisiana. Endothelial dysfunction and inflammation are common etiological pathways for rapid CKD progression and excess CVD risk among CKD patients. The proposed randomized controlled trial will test the safety and efficacy of combination therapy with sodium nitrite and isoquercetin on endothelial function and inflammation among CKD patients. We will recruit 70 albuminuric CKD patients and randomly assign them to combination therapy with sodium nitrite and isoquercetin or placebo for three months. The primary study outcome is endothelial function assessed by brachial artery flow-mediated dilatation (FMD). Our study has 80% statistical power to detect a 2.8% difference in FMD with a 2-sided significance level of 0.05. This study will generate necessary pilot data for an NIH-supported clinical trial to test the efficacy of combination therapy with sodium nitrite and quercetin on CKD progression.

Unintentional overfeeding of formula fed infants
L. Anne Gilmore, PhD, RD, LDN, Pennington Biomedical Research Center
Leanne Redman, PhD, FTOS, Pennington Biomedical Research Center

Despite an almost identical energy density between infant formula and breastmilk, formula fed infants experience greater weight gain in the first year of life. We propose that unintentional overfeeding, of nearly one additional day of calories per week, due to the "over-scooping" of powdered formula contributes significantly to this phenomenon and potentially to the early development of childhood obesity, a significant public health problem. Research of US infants indicates that infant formula use is most prevalent in families with lower levels of education and poverty and as such infant formula is provided to families within the National Women, Infants and Children program. Thereby, the proposed project will examine the health literacy of individuals in the understanding of infant feeding and in particular in the preparation of infant formula. Infant preparation instructions will be modified in through qualitative research to make them more understandable and actionable with an aim of improving caregiver ability to accurately prepare infant formula without overfeeding. The impact of modified formula instructions will then be tested in a randomized controlled trial in comparison to existing commercially instructions provided on the most used brand of infant formula in the US. This is a novel translational study which if successful will demonstrate that with easier to follow preparation instructions, caregivers will less likely overfeed infants resulting in decrease infant adiposity and risk for childhood obesity.

Round 5 Pilot Projects

Adipose Stromal Cells from Obese Donors Promote Tumorigenesis and Metastasis of Breast Cancer
Bruce Bunnell, PhD, Tulane University

Co-Principal Investigator: Matthew Burow, PhD, Tulane University

The negative impact of obesity on human health is clear. Presently in Louisiana over 35% of adults are obese (BMI ≥ 30). If you look at rate of obesity in Louisiana by race 30.5% of Caucasians and 43.2% of African Americans are impacted. Obesity is directly linked to an increased cancer incidence, progression and patient mortality in a number of cancer types including breast. In Louisiana, the number of cases of obesity
related cancers is more than 70,000 per year and it is projected that by the year 2030 that incidence will increase to more than 170,000 per year. Obesity significantly increases breast cancer mortality particularly in "Triple Negative Breast Cancer" (TNBC) which is defined by a lack of estrogen receptor (ER), progesterone receptor (PR), and Her2/Neu over-expression. TNBC occur more frequently in younger patients, are more aggressive than other molecular subgroups and have a higher prevalence in African-American women. Understanding the mechanisms by which obesity affects breast cancer progression and patient survival is a significant public health issue with clear health disparities in Louisiana. Our collaborative team has designed experiments that will clarify the role obesity plays in the tumor microenvironment and specifically in TNBC progression and metastasis. We have defined a previously unrecognized role of adipose stromal/stem cells (ASC) in controlling breast cancer progression and metastasis. ASCs are stem cells of mesenchymal origin found in adipose tissue that give rise to adipocytes. During the development of breast cancer, these cells are recruited to the tumor and are essential components of the tumor stroma. Our preliminary data demonstrates that both tumorigenesis and progression are the result of communication between the stroma and the tumor cells. We found that obesity fundamentally alters adipocyte and ASC biology, and that the cross -talk
between obesity altered ASCs and tumor cells results in a dramatic induction of tumor growth, progression and metastasis. A thorough understanding of the impact of obesity on these tumor stroma interactions and ultimately tumor incidence and progression is of great significance. The objective of this pilot proposal is to define the molecular pathways by which obASC directly alter the tumorigenicity and metastasis of BC tumor microenvironment. The data collected form these preliminary studies will provide essential data on the impact of ASCs from obese individuals on TNBC, which impacts the African-American population, using patients collected from Louisiana citizens.

Using a Community-Favored Alternative Research Design to Study How Neighborhoods May Be Promoting Health Disparities
Stephanie Broyles, PhD, Pennington Biomedical Research Center

Co-Principal Investigator: Robert Newton, PhD, Pennington Biomedical Research Center

This study is unique in that it aims to examine experimentally whether children who live in neighborhoods less supportive of physical activity – having higher crime and lower access to parks – experience lower increases in physical activity when they participate in an intervention. Also, this study explores using a novel, community-favored research design that provides scientific rigor on par with traditional designs, while also allowing all participants to receive the intervention. Results will support a larger study to answer the question of whether the environment can impact a physical activity program's success and will identify ways to promote physical activity in unsupportive environments.  Because poorer and minority populations tend to live in less-supportive neighborhood environments, these results will be important for efforts to reduce health disparities in physical activity and related diseases. 

Cross-generational Cardiovascular Risk Factors: Bogalusa Daughters
Emily Harville, PhD, Tulane University

The Developmental Origins of Disease hypothesis has spurred increased interest in how prenatal exposures affect lifelong health.  In this project, we will draw upon the data, specimens, and infrastructure of the Bogalusa Heart Study, a long-running study of life-course cardiovascular health in semirural, biracial population (65% white and 35% black).  The study provides a research base with unique information about multigenerational influences on cardiovascular health.  Our specific aims are:  1) To examine the relationship between mother's pre-pregnancy and daughter's adolescent/young adult cardiovascular health; 2) To examine whether a woman's cardiovascular health predicts birth outcomes of their grandchildren; and 3) To examine the relationship between mother and daughter's reproductive health.  Pre-pregnancy weight, blood pressure, lipids, and glucose levels and pregnancy weight gain will be examined separately and jointly as predictors.  This project will provide insight into health disparities for important outcomes such as obesity, diabetes, high blood pressure, and low birthweight, that have high prevalence in Louisiana.

Lifespan Cardiovascular Exposures and Risk of Brain Injury in the Bogalusa Heart Study
Lydia Bazzano, MD, Tulane University

Co-Principal Investigator: Owen Carmichael, PhD, Pennington Biomedical Research Center

Cardiovascular disturbances accumulating throughout the lifespan promote sub-clinical brain injury later in life, increasing risk for adverse outcomes including cognitive decline, dementia, stroke, depression, gait disturbance, and early mortality. Unfortunately, the relationship between cumulative exposure to cardiovascular conditions and brain health is under-studied due to difficulty in prospectively collecting cardiovascular data across the lifespan. The Bogalusa Heart Study has >40 years of detailed assessments from childhood through adulthood in a semirural, biracial community, and since 2012, cognitive performance. In the proposed project 50 participants with varying lifespan cardiovascular risk will undergo MRI, including measures of brain tissue volumes, lesion burden, white matter integrity, infarction, cerebral perfusion, and functional and structural connectivity. The association between cumulative cardiovascular exposures and MRI-based measures of brain injury will be assessed to determine optimal design of the definitive study that systematically determines how lifespan exposures impact brain health in the entire cohort of 1,298 participants.  

Clinical Impact of Ethnic Variation in Mitochondrial Function on Hypertension
David Krzywanski, PhD, LSUHSC-Shreveport

Hypertension is an increasing health concern in the United States and African Americans are at a higher risk for hypertension, develop hypertension at an accelerated rate, and are more likely to have uncontrolled hypertension in spite of treatment.  Reactive oxygen species (ROS) are important mediators in hypertension development and a limited number of studies support ethnic differences in ROS production demonstrating that African American cells produce more ROS compared to Caucasians.  We hypothesize that ethnic variation in mitochondrial function and increased ROS production in monocyte/macrophages contribute to hypertension by promoting vascular inflammation and ultimately vascular and renal dysfunction. Our proposed study will be the first to investigate how variation in mitochondrial function contributes to hypertension amongst ethnicities in healthy and hypertensive individuals.  Results from these studies may identify novel therapeutic targets for the development of individual treatment strategies for those with increased incidence of or resistant hypertension.

Developing New Ceramide Analogs as Therapeutic Agents Against AIDS-related Lymphomas
Zhiqiang Qin, MD, PhD, LSUHSC New Orleans

HIV+ individuals have a greatly increased risk of developing malignancies including AIDS-related lymphoma (ARL), which is currently the most common type of cancer in HIV+ individuals in the USA. ARL have a variety of subtypes, such as Diffuse large B-cell lymphoma (DLBCL) and Primary effusion lymphoma (PEL), many of which are related to oncogenic virus Epstein-Barr virus (EBV) or Kaposi's sarcoma-associated herpesvirus (KSHV) infection while still lacking of specific treatment. Ceramide serves as a central mediator in sphingolipid metabolism and is referred to as a "tumor suppressor lipid", however, its role in ARL and therapeutic evaluation remain largely unknown. In the current study, we plan to assess the anti-cancer activities of our newly synthetic ceramide analogs as "lead-compounds" in ARL especially those virus-associated subtypes in vitro and in vivo, as well as understand the underlying mechanisms.

Assessment of Unmethylated Insulin DNA with Droplet Digital PCR in Adolescents with Type 2 Diabetes Compared to Adolescents with Type 1 Diabetes and without Diabetes
Daniel Hsia, MD, Pennington Biomedical Research Center

Droplet digital PCR (ddPCR) is an advanced technology which has been applied to detect circulating insulin gene DNA in the bloodstream. The only significant source of insulin gene DNA is through death of pancreatic β-cells; therefore, the level in the bloodstream is proportional to the degree of β cell death. This technology has been applied to patients with type 1 diabetes and their relatives as a marker of β cell decline. Type 2 diabetes diagnosed during adolescence appears to be more aggressive compared to diabetes diagnosed during adulthood. One hypothesis is that loss of the insulin-producing cells (β-cells) in the pancreas contributes to early treatment failure. The purpose of this pilot study is to validate the ddPCR technology and to determine the degree of β-cell death in adolescents with type 2 diabetes in correlation with β-cell function measured via a mixed meal tolerance test. The ability to identify this pathophysiology in adolescents with type 2 diabetes may be important in determining more aggressive treatment earlier in the disease course and could predict early future complications.

Can Carnitine Supplementation Suppress Fructose-induced de Novo Lipogenesis (DNL)?
Randall Mynatt, PhD, Pennington Biomedical Research Center

Co-Principal Investigator: Eric Ravussin, PhD, Pennington Biomedical Research Center

This proposal is an interdisciplinary collaboration with the goal of testing in humans (Ravussin) the exciting preclinical observation (Mynatt) of the beneficial effect of carnitine supplementation on metabolic health.  Over consumption of high fructose corn syrup is a risk factor for the development of obesity, diabetes, and the transition from fatty liver to NAFLD and NASH. Many of the deleterious effects of fructose consumption are caused by the rapid and largely unregulated oxidation of fructose by the liver causing acetyl-CoA overload and increased DNL. Dr. Mynatt’s preclinical data demonstrates that L-carnitine robustly scavenges excess acetyl-CoA as acetyl-carnitine. In a randomized clinical trial, we will test the ability of carnitine supplementation to suppress fructose-induced DNL. This will be the first clinical study to test the ability of carnitine supplementation to reduce fructose toxicity. This pilot project translates PBRC animal model findings to human subjects and will provide preliminary clinical proof that carnitine may improve metabolism

A Pilot Study to Improve Patient Outcomes Among Breast Cancer Patients by Increasing Early Detection and Intervention of Cardiotoxicity
Tekeda Ferguson, MPH, MSPH, PhD, LSUHSC-New Orleans

In conjunction with women being diagnosed earlier with breast cancer and a rapidly aging population, advances in cancer therapies have swiftly propelled cardiotoxicity as a major health concern. Early markers of myocardial change are a necessity to identify patients experiencing cardiotoxicity so interventions to preserve and save myocardial function can be employed. The proposed pilot study will determine the feasibility of early detection and treatment of cardiotoxicity of three prevalent breast cancer chemotherapy regimens in a sample of 20-25 stage 1-3 primary site breast cancer patients initiating chemotherapy without prior radiation therapy. Cardiotoxicity will be determined by biomarkers and echocardiography measuring global longitudinal strain. Patients will be followed prospectively with data ascertainment at baseline, after the 2nd and 4th chemotherapy cycles of chemotherapy. Patient and physician focus groups will also be used to collect qualitative data regarding patient experiences and physician  practices.  This study will start to address the priority of maximizing benefits while reducing cardiac risks in oncologic management and survival.

Round 6 Pilot Projects

Biological Predictors of Poor Surgical Outcomes Associated with Total Knee Arthroplasty
Christopher Marrero, MD LSU Health Sciences Center – New Orleans

Knee osteoarthritis (OA), a major health problem in Louisiana, involves cartilage degradation and joint inflammation. Total knee arthroplasty (TKA), standard treatment for end-stage knee OA, is performed about 100 times annually at LSU. Preliminary data from LSU patient-reported outcome (PRO) measures show that black patients report more aggravated OA symptoms and difficulties during TKA recovery than white patients. We hypothesize that race-specific biological differences that control inflammation play an important role in disparities in TKA response by race. This project will investigate 1) the relationship between race and inflammatory biological markers, and 2) the extent to which race-related biological markers are associated with OA severity and TKA outcomes. We will analyze tissues and fluids from black and white patients to evaluate differences in levels of inflammatory markers prior to and following TKA and correlate results with PRO scores to determine if biology plays an important role in disparate TKA outcomes.

Molecular signature in whole blood RNA: Novel biomarker for treatment decision of castration resistant prostate cancer
Koji Tsumagari, PhD, Tulane University

Although the overall incidence of prostate cancer (PC) has declined continuously, the incidence of metastatic PC increased by a dramatic 70% during the same time. PC is known as an androgen-dependent malignancy and patients with advanced and metastatic prostate cancer are typically treated with androgen-deprivation therapy (ADT) to block androgen receptor (AR) activity. Although most patients respond favorably to ADT initially, ultimately treatment resistance will develop giving rise to castration-resistant prostate cancer (CRPC) that is lethal within a period of a few years. While 2nd generation AR targeting treatments, enzalutamide or abiraterone acetate, have been approved by FDA for advanced CRPC and generally improve progression-free survival, however, almost all patients eventually develop acquired resistance. Therefore, biomaterials easily obtained for guiding subsequent treatment efficacy are urgently needed. In this study, we plan to identify emergent molecular signatures associated with resistance to AR targeting therapy in whole blood.

Evaluation of Obese Derived Adipose Stem Cell Matrix in the Induction of Luminal B Breast Cancer Endocrine Resistance
Elizabeth Martin, PhD, LSU A&M

The purpose of the study is to test the overall hypothesis: Obese adipose stem cell (ASC) cross talk with ER+ breast cancer induces endocrine resistance. Specifically we aim to determine if ASCs from obese populations respond to stimulatory signals from ER+ breast cancer through the remodeling of the tumor microenvironment. This will be determined through 1) the identification of obese ASCs as the cell source for altered matrix protein expression and matrix alignment and 2) identification of novel therapeutic targets enhance sensitization of ER+ breast cancer to endocrine therapy. Taken together, results from this study will lead to the justification of future studies focused on tissue acquisition of patient tumor samples and identifying trends between tumor matrix composition and patient BMI. Ultimately, we aim to identify patients diagnosed with luminal B and endocrine resistant breast cancers that would have a favorable response to adjuvant treatments such as integrin based agonists.

Obesity and Triple Negative Breast Cancer in Louisiana: Linking Health Disparities and Cancer Biology
Fohkrul Hossain, PhD, LSU Health Sciences Center – New Orleans

The incidence of Triple Negative Breast Cancer (TNBC) and obesity in Louisiana is among the highest in the nation, particularly among African American women. Numerous epidemiological studies reveal an association between obesity and risk of TNBC, however conclusive studies are needed in the Louisiana population. The overall goal of the project is to identify the degree to which social determinants of health and behavior are associated with obesity-related disparities and correlated with TNBC progression and the possible mechanisms whereby obesity can affect the immunological milieu of TNBC through chronic inflammation. Achieving this goal will expand our understanding of how modifiable factors in the neighborhood physical and social environment influence the risk of TNBC, which will enable the development of targeted public health interventions and public policy for precision prevention.

Human Validation of Novel Vaccines and Monoclonal Antibodies to Prevent or Treat Pneumocystis Pneumonia
Sanbao Ruan, MD, LSU Health Sciences Center – New Orleans

Pneumonia due to Pneumocystis jirovecii (PCP) is the second most frequent life-threatening invasive fungal infection worldwide. A vaccine to prevent PCP would be the most cost effective solution to control this infection. To date no successful vaccine or antibodies have been developed against Pneumocystis jirovecii. We have identified and patented a novel vaccine candidate, SPD1, and have confirmed that SPD1 is immunogenic in mice and has protective efficacy as a vaccine. Building on this work, we have identified and patented two novel vaccine candidates in P. jirovecii (PJ-SPD1 and PJ-SPD2) based on similarity at the amino acid level between P. murina and P. jirovecii. We here propose to identify the most promising human vaccine candidate among our SPD1 proteins by this project. The goal of this project is to validate SPD1 proteins as vaccines and as targets for monoclonal antibodies to prevent or treat Pneumocystis pneumonia in human subjects.

The effects of alcohol consumption on central adiposity and testosterone following weight loss in humans
John Apolzan, PhD & Ursula White, PhD, Pennington Biomedical Research Center

Alcohol consumption is one of the most widely used recreational substances and is consumed regularly by much of the U.S. population. Yet, the metabolic effects associated with its use have not been firmly established. The objective of the proposal is to enroll women with obesity to undergo an 8-week, controlled, 30% energy restricted feeding intervention to test the effects of chronic alcohol consumption on changes in abdominal adipose tissue distribution (MRI) and changes in circulating testosterone from baseline. Exploratory aims will measure ectopic lipid (1H-MRS) and assess parameters of the metabolic syndrome (i.e. HOMA-IR, triglycerides, HDL cholesterol, blood pressure, and waist circumference). We hypothesize that participants in the ethanol group will have an attenuated loss of abdominal adipose following a weight loss intervention and increased plasma testosterone, as compared to the control group. Therefore, alcohol consumption may influence fat distribution, with sex hormones as a potential mechanism for these effects.

Clinical Safety and Pharmacokinetic Evaluation of Naringenin: Single Dose Escalation Randomized Double Blind Controlled Trial
Candida Rebello, PhD, Pennington Biomedical Research Center

Naringenin, a citrus flavonoid, improves insulin sensitivity in rodents. Our in vitro studies in human adipocytes corroborate this evidence. The aim of this study is to examine insulin sensitivity in humans treated with naringenin. The hypothesis is that naringenin will improve glucose metabolism.

Targeting Inflamm-aging in Preventing Prostate Carcinogenesis
Qiuyang Zhang, PhD, Tulane University

Prostate cancer (PCa) is mainly a disease of older men. But there is little understanding of how age contributes to PCa. Aging is characterized by a chronic, low-grade inflammation, termed “Inflamm-aging”. Data supporting the role of inflammation in PCa comes from a variety of fields. However, the causal relationship between in-flamm-aging and PCa is unknown. Recent studies have shown that the T helper (Th) 17 immune responses are elevated in aging humans and mice and describe a reciprocal relationship between Th17 and T regulatory (Treg) cells. We hypothesize that inflamm-aging-related elevated Th17 immune responses and Th17/Treg im-balance promotes prostate carcinogenesis. Our objective is to determine whether and how Th17 immune re-sponses and Th17/Treg imbalance play a role in PCa development in aged versus young PCa mouse models. These studies will help us understanding of how inflamm-aging promotes PCa and to find new targeted thera-peutic interventions against PCa in the elderly.

Molecular Mechanisms of a Tissue Selective Estrogen Complex (TSEC) on Muscle and Adipose Tissue in Postmenopausal Women
Dragana Lovre, MD, Tulane University

The combination of conjugated estrogens (CE) with bazedoxifene (BZA) is a new menopausal hormone therapy that provides the advantages of estrogens without the use and side effects of a progestin. A pre-clinical study showed that CE/BZA prevents estrogen deficiency-induced metabolic dysfunction by increasing fat oxidation and energy expenditure. Currently, there is no data on the efficacy and molecular mechanism of CE/BZA in preventing metabolic disorders in postmenopausal women. My hypothesis is that CE/BZA will improve ectopic fat and insulin sensitivity. To test my hypothesis, I propose to characterize the molecular mechanisms of CE/BZA action using biopsies of post-menopausal women treated with CE/BZA for 8 weeks including skeletal muscle, adipose tissue and hepatocyte clonal cell line of women. I will examine pathways of insulin and energy metabolism. This laboratory exposure will expand my knowledge of the basic mechanism of estrogen actions on metabolism and translational research techniques as part of my career development path to an independent investigator.

Round 7 Pilot Projects

Promoting Cardiovascular Health and Reducing Disparities with Native Americans
Catherine Burnette, PhD LMSW, Tulane University

Alcohol and other drug (AOD) abuse and violence in families are co-occurring risk factors for cardiovascular disease (CVD), diabetes, and other chronic diseases–all health disparities of Louisiana residents. These factors drive mortality among Native Americans (NA) who are among the most invisible and understudied groups of the region. With a sample of NA Tribal members of the Southeast, this research will begin to develop a culturally adapted intervention with a mobile health (mhealth) component that will address the primary risk factors of poor nutrition, AOD abuse, and violence in families. This one-year project will: (a) use ethnographic interviews with Tribal community members to identify culturally specific protective factors related to diet and well-being, including physical health, psychological health, social health, and spiritual health, and (b) use a community-based participatory research (CBPR) approach with a community advisory board (CAB) to begin to develop a culturally adapted intervention.

Feasibility of Electronic Health Records to Study Social Determinants of Health Disparities in Hepatocellular Carcinoma in Louisiana
Claudia Leonardi, PhD, LSU Health Sciences Center – New Orleans

In the US, Hepatocellular Carcinoma (HCC) incidence has tripled over the past two decades and is expected to become the third leading cause of cancer deaths by 2030. This trend indicates that social determinants are driving the epidemic at the population level. Additionally, the disease has disproportionately affected minority and disadvantaged populations. The overall goal of this project is to assess the representativeness of HCC cases included within an electronic health records (EHR) network, assess the feasibility of attaining their clinical risk factors associated with the rise in HCC and identify controls within the EHR network. These efforts will enable future studies investigating the degree to which social determinants of health in the physical and social environment are associated with HCC incidence and related disparities. Achieving this goal will allow us to seek further understanding of how modifiable factors in the neighborhood physical and social environment influence the risk of HCC, which will enable the development of targeted public health interventions and public policy for precision prevention.

Alcohol Use in People Living with HIV: Impact on Mitochondrial DNA Damage and T-Cell Immunosenescence
Robert Siggins, PhD, LSU Health Sciences Center – New Orleans

Inflamm-aging is common to both Human Immunodeficiency Virus (HIV) infection and chronological aging. Our data show that alcohol use disorders (AUD) and chronic binge alcohol (CBA) aggravates inflammaging in HIV-infected individuals and SIV-infected rhesus macaques. Aging, HIV, and AUD are individually associated with mitochondrial dysfunction. Preliminary data suggest CD8+ T-cell immunosenescence is linked to mitochondrial “health”. We hypothesize that CBA and SIV/HIV synergistically damage mitochondria, accelerating immunosenescence and inflamm-aging in CD8+ T-cells. We will examine T-cells from SIV+, ART+ macaques ±CBA and human PBMCs in vitro ± HIV, ± ART, and ± alcohol to assess mtDNA damage and how this correlates with senescence and activation. Additionally, we will determine the role of mitochondrial damage in promoting CD8+ T-cell activation and senescence. We will measure mitochondrial damage, redox status, telomere length, and immunosenescent T-cell phenotypes. This proposal explores an innovative mechanism explaining how alcohol misuse leads to immune aging in PLWH.

The Role of Extracellular Vesicle Carried MiRNAs on Colorectal Cancer
Aaron Klinger, MD, Ochsner

Colorectal cancer (CRC) prognosis is dependent on tumor depth, lymph node (LN) involvement, and extranodal metastasis. The LN stromal microenvironment may affect metastasis via extracellular vesicle (EV)-mediated communication. EVs carry micro-RNAs (miRNAs), small non-coding RNAs that alter gene expression by targeting mRNAs. Here we aim to identify specific miRNAs carried by LN stromal cell (LNSC) EVs that alter progression of CRC. Total miRNA sequencing was performed on HK (a LNSC line) cells and HK-EVs, mesenteric LNSCs and LNCS-EVs, and 5 well studied CRC cell lines using Next Generation Sequencing. These findings will be confirmed by PCR and miRNAs overexpressed in HK cells, LNSCs and their EVs compared to CRC cell lines will then be further analyzed using in silico prediction models. Using commercially available miRNA mimics and inhibitors we will next analyze the roles of these selected miRNAs in vitro and then in vivo using our patient-derived orthotopic mouse model.

Real-time Mass Spectrometry and Lipidomic Analysis in Liver Transplantation
John Seal, MD, MA, Ochsner

Expanded utilization of organ donors in liver transplantation is hindered by an inability to accurately predict which grafts will function adequately in the recipient, leading to discard of potentially life-saving organs. Recent development of rapid evaporative ionization mass spectrometry (REIMS) allows for real-time analysis of tissue by capturing the vapor from commonly used electrosurgical devices and is ideally suited for clinical applications. The proposed study will focus on (1) application and validation of REIMS for liver allograft assessment in surgery and (2) lipidomic analysis of fatty donor livers. The obesity epidemic has had a major impact on the prevalence of fatty liver disease in potential organ donors, particularly in Louisiana. Using a cross-disciplinary approach, we will leverage my collaborator’s expertise in mediator lipidomics in neuroscience to explore lipid homeostasis in the context of donor hepatosteatosis with the aim of identifying potential biomarkers for risk-stratification of fatty donor livers.

The role of estrogen in adipocyte remodeling following surgical menopause
Kara Marlatt, PhD, MPH, Pennington Biomedical Research Center

Menopause is characterized by a dramatic decline in estrogen levels with commensurate weight gain and a preferential increase in abdominal fat. Given the stochastic nature of ovarian function during natural menopause, the impact of estrogen loss on weight gain and body fat redistribution is difficult to interpret. Bilateral oophorectomy (or ‘surgical menopause’) offers a unique opportunity to examine the direct role of estrogen loss on body fat redistribution in women. In this proof-of-concept study, we will enroll 8 pre-menopausal women (follicle-stimulating hormone, FSH<40 mIU/mL and asymptomatic for menopause-related symptoms). We will test the hypothesis that abrupt loss of estrogen following elective bilateral oophorectomy increases the rate of adipogenesis (via deuterium-labeling to measure adipocyte formation) in the subcutaneous abdominal depot (and possibly the subcutaneous femoral depot) compared to non-oophorectomized women with normal menstrual cycles, which will be associated with altered adipose tissue gene and protein expression.

Disruption of the circadian melatonin signal by dim light at night promotes bone lytic breast cancer metastases
Muralidharan Anbalagan, PhD, Tulane University

Our preliminary studies demonstrate that luminal A MCF-7 breast cancer cells, which are poorly invasive and low expressers of CXCR4, when injected into the tibia of Foxn1nu mice housed in a dim light at night (dLAN) photoperiod (dLAN inhibits/suppresses nocturnal MLT production) develop full blown tumors that are associated with significant osteolytic lesions. However, treatment of these osteolytic tumors with Dox in alignment with exogenous nighttime MLT induced significant tumor regression and bone remodeling after just three weeks. Based on our published work and these preliminary studies, we propose studies that will test the hypothesis that ‘Disruption of the circadian nocturnal MLT signal by exposure of mice to dLAN promotes the development/progression of metastatic breast cancer bone lesions and treatment with Dox in circadian alignment with MLT reduces/inhibits metastatic tumor burden and lesions in bone, and enhances bone remodeling’.

Assessing Exposures to Arsenic and Other Inorganic Chemicals in Unregulated Private Wells in Southern Louisiana: Implications to Human Health
Tewodros Godebo, PhD, Tulane University

Nearly half the population of Louisiana receives drinking water from groundwater resources, and an estimated 587,500—representing 13% of the state’s population—gets drinking water from privately owned domestic wells. These wells are excluded from the EPA’s drinking water monitoring requirement for more than 85 contaminants including Arsenic (As). Arsenic is a toxic chemical that occurs widely in the environment and is known for its neurologic and carcinogenic effects. The U.S. Geological Survey (USGS) first reported elevated As levels in domestic wells in southern Louisiana in 2003. Subsequent small-scale surveys in Cow Island, Forked Island, and Opelousas found As above the EPA’s standard of 10µg/L, with the highest value of 60µg/L. This highlights the health issue that thousands of private wells in the state are potentially contaminated with one or more toxic chemicals including As, lead (Pb), mercury (Hg), and fluoride (F─)—with important health implications. This pilot study focuses on the aquifer systems around Lake Pontchartrain that host many unregulated private wells. Additional contamination may occur from crops locally grown in high As-containing soil. This contamination results from the legacy of arsenical pesticide use primarily in cotton fields and raises additional exposure and related health concerns for the residents. The goal of this research is to obtain a better understanding of the risks of As and other inorganic contaminants exposure of households utilizing unregulated private wells around Lake Pontchartrain. This goal will be accomplished by determining the distribution of trace elements in water, local grain crops, and assessment of biomarkers in fingernail clippings and urine samples that will enable us to estimate individuals’ exposure from all sources (water and food). This seed fund will help the PI, Dr. Godebo, to develop new research infrastructure in the state that will be critical to generate preliminary data to apply for additional funding from other sources, including from the National Institutes of Health (NIH), focused on studying adverse health outcomes of potential chemical exposures in the study area and extending to other parts of Louisiana.

Round 8 Multi-Institutional & Diabetes Focused Pilot Projects

Obesity, Health Disparities and Cancer Risk in Louisiana
Peter Katzmarzyk, PhD, Pennington Biomedical Research Center
Jovanny Zabaleta, PhD, LSUHSC-New Orleans

The long-term goal of this project is to increase our understanding of the association between obesity and cancer in our high-risk, underserved Louisiana population, and to identify the roles of sex, race and cancer genes in modifying this association. The aim of this project is to link data from approximately 19,000 participants in the Pennington Center Longitudinal Study (66% White, 34% African American) to the National Death Index and the Louisiana Tumor Registry to investigate associations among adiposity and cancer mortality and incidence. A further goal is to test selected participants for cancer genes to explore how their genetics modify associations between obesity and cancer. This work will be accomplished through a partnership between the Pennington Biomedical Research Center and the LSU Health Sciences Center in New Orleans. The results will provide new information on cancer biology and identify new ways to improve cancer prevention and survival.

Confluent Disparities in Modifiable Health Behaviors in People Living with HIV throughout Louisiana
David Welsh, MD, LSUHSC-New Orleans
Lauren Richey, MD, MPH, LSUHSC-New Orleans
John Apolzan, PhD, Pennington Biomedical Research Center
John Vanchiere, MD, PhD, LSUHSC-Shreveport

The long-term goal of our research collaborative is to mitigate the disparities in adverse health behaviors in people living with HIV (PLWH) in order to reduce comorbidities and poor health outcomes. The overall objective of this proposal is to generate sufficient preliminary data, and to establish a research collaborative, to support a successful federal research funding application to test interventions targeting confluent adverse health behaviors in order to improve the health of PLWH. Our hypothesis is that interventions designed to reduce smoking and other substance use, increase physical activity, and/or modify dietary selection will reduce comorbidity in PLWH. We will study this in HIV-specific clinics in Shreveport, Baton Rouge, and New Orleans. An improved understanding of the interrelatedness of these behaviors, and the barriers to implementation of treatment, will inform interventions that offer the potential to significantly improve the health and quality of life of PLWH.

Evaluating glial acetate metabolism as a biomarker of hypoglycemic complications in patients with type 1 diabetes: A proof of concept study
David McDougal, PhD, Pennington Biomedical Research Center
Vivian Fonseca, MD, FRCP, Tulane University

Hypoglycemia-associated autonomic failure (HAAF) is a condition commonly developed in diabetic patients, which often causes life threatening bouts of hypoglycemia. These hypoglycemic crises are a significant impediment to the maintenance of healthy blood glucose levels in individuals with diabetes. HAAF is thought to be driven by cellular or metabolic adaptations in the brain which alters its response to hypoglycemia. Cross-sectional studies have previously demonstrated an association between glial acetate metabolism (GAM) and susceptibility to hypoglycemia. The PIs prior study, GLIMpSE, was the first interventional study that demonstrated that exposure to hypoglycemia would lead to increases in GAM. Furthermore, these data demonstrated that GAM was predictive of susceptibility to future hypoglycemic events, and thus showed promise as a biomarker. The current proposal will build on these preliminary findings to further investigate the relationship between GAM and hypoglycemia in a targeted patient population known to experience treatment-induced hypoglycemia, individuals with T1DM.

Round 9 Pilot Projects

Engineering T cells to target Klebsiella pneumoniae infections
Janet McCombs, PhD, Tulane University

Klebsiella pneumoniae infections cause millions of deaths worldwide each year, with a particular impact on immunocompromised patients such as those with diabetes or undergoing organ transplant. Due to increases in antibiotic resistance, therapeutic options toward K. pneumoniae are limited, underscoring the need for alternative treatment strategies. The objective of this work is to design an immunotherapeutic approach for clearing K. pneumoniae infection through genetically engineered T cells. We propose engineering T cells to express T cell receptors specific to K. pneumoniae antigens will provide targeted cellular therapy for these infections. To address this hypothesis, this work will 1) design and characterize engineered T cells expressing artificial TCRs that specifically recognize K. pneumoniae and 2) demonstrate efficacy of polyclonal and engineered T cells in an in vivo K. pneumoniae infection model. Overall,

Accomplishing these claims will establish an adaptable technique for development of therapies toward a multitude of bacterial pathogens.

Developing a bile acid biomarker to predict the efficacy of fecal microbiota transplantation in overt hepatic encephalopathy
Amy Feehan, PhD, Ochsner

Between 2013-2020, Ochsner Health System (“OHS”) diagnosed 18,321 patients with cirrhosis of the liver, and over 1 in 5 of those patients went on to develop hepatic encephalopathy (HE), a condition which causes impaired neurotransmission and inflammation that leads to cognitive impairment. Fecal microbiota transplantation (FMT) improves cognition in HE by reducing inflammation and increasing conjugation of primary BAs into secondary BAs [1-3]. At Ochsner, we are conducting an ongoing phase 2 clinical trial (NCT04155099) of an FMT oral formulation for patients with HE and banking serum samples at baseline, 1, 3, and 6 months. The proposed study will use banked samples to examine whether bile acids (BAs) can successfully predict recovery

following FMT. We hypothesize that in patients with HE, specific BAs or a BA signature (1) change in a dose-dependent manner following FMT, (2) can predict efficacy of FMT treatment, and (3) co-vary with inflammatory markers.

The role of macrophages colonization by Neisseria gonorrhoeae (N.g) during gonorrhea development
Ana-Maria Dragoi, PhD, LSU Health Sciences – Shreveport

We propose to investigate the role of macrophages colonization by Neisseria gonorrhoeae (N.g) during infection and the impact on gonorrhea development. Rising incidence and increasing antibiotics resistance highlights the need to understand the molecular basis of N.g pathogenesis and the need for new therapeutic targets. Louisiana has the third highest rate of gonorrhea infection in the country, second only to Mississippi and Alaska. Because N.g is a highly human adapted pathogen, it has developed numerous mechanisms to counteract the immune responses. Macrophages are present in significant numbers throughout the genitourinary mucosae and represent 10% of total number of leukocytes recovered from these tissues. Thus, it’s likely that N.g encounters these cells during infection and that macrophages play an important role in N.g pathogenesis. Here, we will assess the presence and the function of macrophages in human cervico-vaginal lavage samples and test four repurposed drugs as novel therapy for gonorrhea development.

Epigenetic analysis of regulation of the inflammosome-activating NLRP3 gene in monocytes from atrial fibrillation patients and controls
Sruti Chandra, PhD, Tulane University

The enhanced inflammatory response driving atrial fibrillation (AF) is associated with priming and activation of the NLRP3 inflammasome, which involves increased synthesis of the sensor protein NLRP3. Elderly women are most prone to AF. Our recent bioinformatic analysis indicates that the highly preferential expression of NLRP3 in leukocytes, and especially monocytes, is associated with a previously unreported formation of a super-enhancer. We found monocyte- specific DNA hypomethylation in two super-enhancer subregions. DNA hypomethylation can be a quantifiable marker of gene expression and can increase with age. We will examine the association of this DNA hypomethylation with NLRP3 expression in leukocyte subtypes and test its association in monocytes with age and AF status in females. DNA methylation and gene expression analysis will be performed by the newly developed Long-Range Enzymatic Methyl-seq and by qRT-PCR, respecti al for upregulation of NLRP3 in AF may offer new potential drug targets.

Assessing the Role of Transferable Exosomal PD-L1 in Renal Cell Carcinoma
Louis Krane, MD, Tulane University

Patients with metastatic renal cell carcinoma have dismal long-term survival, with only 15% of patients alive five years after diagnosis. Immuno-oncologic agents, which activate the patients' own immune system to fight the tumor, have provided durable long-term remissions in in a subset of patients with metastatic renal cell carcinoma, however identifying those patients most likely to benefit from these therapies remains imprecise as there are no biomarkers for response to therapy. Mechanisms of patient resistance to this therapy are poorly understood.

Exosomes are microvesicles derived from cancer cells which transfer both proteins and nucleic acid to other cells. It has been shown they can transfer resistance to cancer therapy between cells, allowing for disease progression. It is not known whether they can transfer agents which are used by tumors to hide from immunologic targeted therapy in kidney cancer. This proposal will use exosomes from patients with metastatic renal cell carcinoma undergoing immuno-onoclogic therapy to determine a specific mechanism for therapy resistance. In addition to determining the in vivo mechanism for therapeutic resistance, we will determine in the laboratory how these exosomes are transmitted between cells to create resistance to immunologic cancer therapy. These insights will broaden our understanding of how exosomes renal cell carcinoma to evade treatment so that therapeutic combinations can overcome this problem in the future.

The role of BID in NAFLD-related metabolic changes of hepatic macrophages
Shengmin Yan, PhD, Tulane University

Non-alcoholic fatty liver disease (NAFLD) is intimately associated with the clinical features of me abolic syndrome. However, approved pharmacological therapy for NAFLD is still absent. Our unpublished study found that genetic deletion of BH3 interacting-domain death agonist (BID) can protect mice against diet-induced obesity and hepatic steatosis, which is intriguingly related to gut microbiota. Macrophages play essential roles in the progression of NAFLD. Our central HYPOTHESIS is that diet-induced gut dysbiosis changes hepatic metabolites which promotes BID- dependent metabolic signatures in hepatic macrophages, and thereby leading to a disrupted innate immune response and NAFLD. Successful completion of this study will identify a novel mechanism of BID in macrophage metabolism in the progression of NAFLD. We anticipate that this study will lead to innovative therapeutic approaches by targeting BID and/or through giving nutrient supplements in patients with NAFLD.

Community opinion of technology supported dietary pattern interventions (CoopTech)
Kristin Hoddy, PhD, Pennington Biomedical Research Center

Modern diet and disrupted chronobiology are independently linked to cardiometabolic dysfunction. We posit that certain dietary interventions, like intermittent fasting (IF), are proxies for enhanced eating regularity via manipulating inputs including meal timing, frequency, and quantity. Our work in IF demonstrates improvements in cardiometabolic health. This coupled with chronobiological literature and existing observations of eating regularity point to the importance of regular dietary patterns. The largest barrier to continued research is the lack of a singular method to quantify eating regularity. As part of our objective, we will develop an eating regularity index (E-REG) using near real-time dietary intake assessment via remote food photography, continuous glucose monitoring, and wrist actigraphy across ?-days of observation. Additionally, eating regularity will be used to cross-sectionally compare participants and qualitative data will ascertain their perceptions of eating regularity, acceptability of technology-supported assessment techniques, and willingness to engage in future interventions.

Round 10 Pilot Projects

Sex Differences in COVID-19 Outcomes: Role of Sex Hormones, Inflammatory Biomarkers, Comorbidities, and Socio-demographic Factors
Yilin Yoshida, PhD, Tulane University

Coronavirus disease 2019 (COVID-19) is characterized by a male predominance in severity and mortality worldwide, but reasons underlying the sex-bias are unclear. Sex differences in comorbidities, sex hormones, and inflammatory biomarkers may all be factors involved in the sex differences of COVID-19 outcomes. However, few studies examined the role of these factors in COVID-19 outcomes stratified by sex. In our recent study in 776 hospitalized COVID-19 adults in New Orleans, we observed sex differences in comorbidities and biomarkers as predictors of COVID-19 severe outcomes. Our study underscores the need for a larger study with sex-stratification and robust analysis to determine if our findings are region-specific or hold generalizability to other populations. We propose to use the rich and population-based National COVID Cohort Collaborative (N3C) data to examine to what extent comorbidities, female sex hormones, and inflammatory biomarkers represent sex-specific determinants of COVID-19 outcomes. This analysis will provide new knowledge of the biological and clinical determinants of COVID-19 severity that may be of clinical utility to healthcare providers for management tailored to women and men. It will generate pilot data to support a larger grant application aiming at elucidating sex disparities in clinical and biological determinants of severe COVID-19 outcomes, thus facilitating a gender-specific approach to risk stratification, prevention, and treatment.

Intestinal Glucose Utilization Drives the Weight Loss Benefits of Roux-en-Y Gastric Bypass
Vance L. Albaugh, MD, PhD, Pennington Biomedical

Even though metabolic and bariatric surgery (MBS) is the most effective treatment for obesity, its powerful yet unknown mechanisms driving long-term weight loss represent a critical node of body weight control. Increased intestinal glucose utilization following MBS with intestinal bypass is one such mechanism that has been identified pre-clinically, and also supported by retrospective patient studies. However, a prospective validation and mechanistic trial has not been conducted to date, which could reveal a powerful new target for treatment of metabolic disease – the intestine. Preliminary data demonstrate significantly more weight loss and maintenance of weight loss over time after MBS with intestinal bypass. In this LACaTS project, we propose a simple, non-randomized clinical trial to (1) validate and characterize intestinal glucose uptake serially following MBS using non-invasive, radiologic imaging and couple this with measurements to (2) estimate the increase in energy expenditure due to intestinal glucose utilization that drives weight loss using whole room energy expenditure. Patients will be identified and recruited from the Bariatric & Metabolic Institute at Pennington Biomedical, where relatively equal numbers of patients undergo MBS operations with and without intestinal bypass. The bariatric surgeon-scientist PI is junior faculty at Pennington Biomedical and has assembled a strong mentoring committee experienced in clinical bariatric surgery research (Schauer), radiologic tracer imaging (Carmichael), and energy expenditure methods (Ravussin). The mentoring committee, state-of-the-art clinical and research facilities, and the well-prepared PI will support the successful completion of the project resulting in major federal research funding and the PIs transition to scientific independence.

Role of mitochondrial quality control in vascular aging
Rutkai Ibolya, PhD, Tulane University

Aging is a major risk factor for neurodegenerative diseases such as Alzheimer’s disease and cerebrovascular diseases. Aging-related changes in the vascular system contribute to decreased cerebral blood flow, promoting cognitive decline in Alzheimer’s disease and other types of dementias. Mitochondria has been found to play an important role in the development of the aging phenotype, likewise vascular pathologies are reported in many patients with Alzheimer’s disease and/or vascular cognitive impairment. The proposed research will reveal how aging and cerebral hypoperfusion affect endothelial mitochondria and will shed light on mechanisms that might precede and contribute to aging-related pathologies such as Alzheimer’s disease.

The Role of Hydrogen Sulfide in Adipose Tissue Microvascular Function in Obesity-Associated Heart Failure with Preserved Ejection Fraction
Timothy Allerton, PhD, Pennington Biomedical

Project will conduct metabolic phenotyping (insulin sensitivity, body composition, metabolic rate) on a cohort of obese patients with and without heart failure with preserved ejection fraction (HFpEF). It will also measure an important vasoactive gas, hydrogen sulfide, in the plasma and adipose tissue to better understand its role in the obese-HFpEF phenotype.

Addressing health disparities in African Americans – exploring sleep and developing interventions
Prachi Singh, PhD, Pennington Biomedical

Sleep disruptions through sleep deficiency and sleep apnea are suggested to contribute to racial disparities in obesity, diabetes, and cardiovascular diseases. Habitual short sleep duration is highly prevalent in Louisiana and more evident in the African American (AA) population. Similarly, sleep disorders such as sleep apnea are not only more common but are also more severe in AAs. However, there are several limitations to sleep disparity research that limit our ability to effectively intervene with this population. First, there is very little data on the effectiveness of interventions in AA participants. This is related to the fact that no sleep intervention study has specifically targeted AAs. Second, recruitment of AAs into sleep research has been traditionally low. For example, the Sleep Heart Health study examined the effects of sleep disturbances on quality of life and included more than 5000 participants of which only 9% were AAs. Similarly, a meta-analysis comparing sleep disorders in Caucasians versus AAs included only ~16% AAs. As a result, factors contributing to poor sleep in AAs are not completely understood. In order to directly address these limitations, there is a need to obtain information documenting AA’s perceptions of sleep as a health issue and willingness to participate in sleep research. A community engaged research approach, which will involve partnerships with community entities to build trust within the community and having direct communication with the target community, can be used to obtain this information and also uncover strategies that may be effective in improving retention and developing robust interventions to improve sleep globally. We propose to assess the local demographics, psychosocial factors, and comorbidities associated with inadequate sleep in AAs via questionnaires. We will also obtain objective and subjective assessments of sleep in order to determine accuracy of sleep self-reporting in this population (Aim 1). Among the study participants with objectively determined poor sleep, we will use a focus group approach to investigate sleep-related perceptions, identify barriers to recruitment and retention for sleep biomedical research in the local AA population, and use community feedback to develop interventions to improve sleep (Aim 2). The goal of the study is to enhance recruitment and retention of AAs in sleep-related clinical research and to develop a holistic tool-kit including sleep-targeted behavior modification to improve well-being in AAs. By achieving the aims, we will determine the feasibility of obtaining sleep-related outcomes, develop strategies to overcome recruitment barriers, assess AA’s willingness to participate, and develop intervention strategies that will benefit sleep research globally.

Characterizing Immune Response in Viral and Non-Viral Mediated Oropharyngeal Carcinomas
Larissa Sweeny, MD, LSU Health New Orleans

In the past two decades there has been an epidemic of human papilloma virus (HPV) related oropharyngeal squamous cell carcinomas (OPSCC). The incidence of HPV related OPSCC has now surpassed that of cervical cancer. Patients with HPV positive OPSCC typically respond more favorably to traditional therapy with improved overall survival compared HPV negative OPSCC. While extensive preclinical work has focused on understanding HPV oncoproteins E6 and E7 (which result in inhibition of apoptosis and cell cycle regulators, such as TP53 and RB1, and extensive DNA damage) there is limited understanding of the immune response to this viral mediated carcinoma and the variance in prognosis between HPV positive and negative OPSCC. Recent advances in our understanding of the immune characteristics of the tumor microenvironment (TME) and the potential therapeutic implications have generated significant interest and excitement. Understanding the immune response within the TME of the viral versus non-viral mediated OPSCC may provide insight into their pathogenesis, lead to targeted treatments and improve treatment effectiveness. It is through correlating the expression of regulatory and metabolic markers and immune response within the microenvironment that we can develop a better understanding of the pathogeneses of these two OPSCC etiologies. We propose a study designed to investigate the impacts of HPV on tumor cell metabolism and immune phenotypes within the TME. We will evaluate expression of proteins related to cell cycle and metabolic pathways (p53, RB1, CD147, MCT1 and 4, HIF) and immune phenotypes (PDL1, LAG3, CD44, and FOXP3) in a preclinical murine model followed by analysis of human samples obtained from OPSCC tumors. This study is intended to advance our understanding of how HPV impacts cancer metabolism and modulates tumor immune response. It is our hope that through an improved understanding of the pathogenesis will come more effective clinical therapies.

Epigenetic signature of obese-induced MDSC: decoding the link with increased risk for Cancer
Maria Sanchez-Pino, PhD, LSU Health New Orleans

Obesity is a state of chronic low-grade inflammation that increases the risk of developing cancer. The mechanisms underpinning the low-grade inflammation are poorly understood. We recently found that myeloid-derived suppressor cells (MDSC) are significantly increased in morbidly obese patients compared to healthy normal-weight controls (NWC). MDSC have been shown to suppress protective T cell and NK cell anti-tumor responses, and therefore may represent a biological link between obesity and cancer risk. We also have shown that the expansion and function of MDSC are in part determined by the cellular metabolism; thus, obese-derived metabolic factors may be key players in modulating MDSC towards their pro-tumor nature. Our preliminary data by comparing the transcriptome of MDSC from patients with obesity and NWC showed significant differences, including several genes of epigenetic modifiers which may provide insights into the functional differences between these obese-induced MDSC, and suggest potential clinical implications.

Preclinical pharmacological evaluation of novel therapeutic compound itaconate for treating ischemic stroke complication in HIV Tg26 mice
Yinghua Jiang, MD, PhD, Tulane University

The number of HIV cases is still rising in the US, particularly in Southern regions. Application of combined antiretroviral therapy to HIV patients (HIV-cART) converts HIV infection to a chronic state with lowering viral replication but largely extending lifespan. However, the HIV-cART patients suffer from side effects, the most common one is metabolic syndrome and associated thrombotic vascular diseases. Particularly, ischemic stroke, as one of the most devastating cerebrovascular complications, features a significantly increased incidence, primarily occurring at younger ages and greatly increased rate of death and disability in such patients. Unfortunately, therapeutic agent specifically targeting such HIV-stroke complication is still lacking. Herein, we have established a mouse model combining chronic HIV state and ischemic stroke in HIV Tg-26 mice. In this project, we aim to further characterize the post-stroke pro-inflammatory pathophysiology and perform a rapid preclinical drug screening to identify potentially effective compounds for IND preparation in HIV-stroke treatment.

miR-145/MMP9 ratio for prediction of recurrence in patients with well-differentiated thyroid carcinoma patients
Eman Toraih, MD, PhD, Tulane University

Despite a favorable rate of survival for well-differentiated thyroid cancer (DTC), the risk of recurrence can reach up to 30%. It is highly challenging to predict which tumors will remain indolent and which will progress and accordingly this affects the decision on who should get adjuvant radioiodine therapy or extensive postoperative surveillance. Hence, it is urgently needed to identify biomarkers that can accurately predict tumor recurrence or persistence in advance. Our long-term goal is to establish a robust and well-validated molecular prognostic marker that identifies which tumors are likely to progress. Given the high stability of exosomes and their ability to embed specific genetic materials that resemble the properties of their originating cancer cells, we hypothesize that quantitation of tumor-derived exosomal RNAs will be a promising prognostic tool to identify tumors that are likely to evolve into more progressive behavior in DTC patients, thus help guide treatment in a more individualized way.

2020-2021 NIH Administrative Supplement

Effects of E-Cigarettes on the Lung Metabolome in People Living with HIV
John Kirwan, PhD, Pennington Biomedical Research Center
John Apolzan, PhD, Pennington Biomedical Research Center
David Welsh, MD, LSU Health Sciences Center-New Orleans
Christopher Taylor, PhD, LSU Health Sciences Center-New Orleans

E-cigarette use is dramatically increasing particularly among underserved populations including people living with HIV (PLWH). E-cigarette, or vaping, product use–associated lung injury (EVALI) highlights the hazards of the uptake of new substance use behaviors without adequate understanding of the medical consequences. The overall objective of the study is to determine changes in lung metabolites associated with e-cigarettes, or vaping, and to examine how gut microbiota moderate vaping associated lung injury markers in PLWH to help discover therapeutic targets.

2014 Multi-Institutional Projects

Cervical Cancer Prevention in Louisiana
Michael Hagensee, MD, PhD, LSUHSC New Orleans - Principal Investigator

Co-Principal Investigators:
William Robinson, MD (Tulane University)
 Amber Naresh, MD, PhD (Tulane University)
Jerry McLarty, PhD (LSUHSC Shreveport)
Holiday Durham, PhD, RD, LDN (Pennington Biomedical)
Donna Williams, MPH, DrPH (LSUHSC New Orleans)
Jennifer Cameron, PhD (LSUHSC New Orleans)

With successful screening programs and appropriate implementation of the HPV vaccines, cervical cancer can be eliminated in the US.  Louisiana ranks fourth in cervical cancer incidence and third in mortality due to limited healthcare resources.  Innovative cervical cancer prevention programs that are sensitive to the unique challenges of limited-resource, health-disparate communities is hypothesized to greatly reduce cervical cancer morbidity and mortality in Louisiana. Four research projects will address this hypothesis by identifying cultural, socioeconomic and treatment factors that promote use of HPV vaccines; evaluating self-sampling with HPV testing as a primary screening alternative; identification of nutritional risk factors that promote regression of low-grade cervical intraepithelial lesions and discovery of novel molecular biomarkers that predict progression of low-grade lesions to high-grade lesions.  These efforts will combine expertise from LSU-New Orleans, LSU-Shreveport, Pennington Biomedical Research Center and Tulane University School of Medicine to reduce the impact of cervical cancer in Louisiana. 

Hydrogen Sulfide Metabolism in Critical Limb Ischemia
Christopher Kevil, PhD, LSUHSCShreveport - Principal Investigator

Co-Principal Investigators: 
David Lefer, PhD (LSUHSC New Orleans)
Albert Sam, MD (Tulane University)

Critical limb ischemia (CLI) represents the extreme progression of peripheral artery disease (PAD) often resulting in limb loss along with a very large increase in cardiovascular mortality due to secondary events such as myocardial infarction or stroke.  Therapeutic options for CLI patients are few and largely consist of surgical revascularization and amputation. Importantly, key pathophysiological contributors to CLI remain poorly understood. Recent experimental studies indicate that the gasotransmitter hydrogen sulfide ameliorates vascular dysfunction and restores ischemic tissue perfusion, yet hydrogen sulfide bioavailability in clinical and experimental CLI remains unknown.  This application will test the hypothesis that hydrogen sulfide bioavailability is significantly decreased in CLI patients and in a large animal model of CLI.  This hypothesis will be tested through the pursuit of two aims that will: 1) measure plasma and tissue hydrogen sulfide metabolite bioavailability in CLI patients, and 2) Determine the effects of a novel H2S-donating agent (i.e., Enalapril-TBZ) in a clinically relevant swine model of Critical Limb Ischemia.  Hydrogen sulfide metabolites will be measured in clinical CLI specimens obtained from LSUHSC-Shreveport and Tulane University SOM, and the Enalapril-TBZ H2S based therapeutic study performed in a swine model of CLI.  Results from this collaborative project will establish the foundation for future clinical research and novel treatment modalities for patients with CLI.

Novel tissue selective estrogen complex with Bazedoxifene and the prevention of metabolic dysfunction in post-menopausal women
Franck Mauvais-Jarvis, MD, PhD, Tulane University - Principal Investigator

Co-Principal Investigator:
Eric Ravussin, PhD (Pennington Biomedical)
Frank Greenway, MD (Pennington Biomedical)

Pairing the selective estrogen receptor modulator, bazedoxifene (BZA), with conjugated estrogen (CE) as a tissue-selective estrogen complex (TSEC), is a novel menopausal therapy. Using a mouse model of post-menopausal metabolic syndrome, we recently reported that TSEC prevent estrogen deficiency-induced metabolic dysfunction without causing endometrial hyperplasia. We found that CE, BZA or TSEC increased energy expenditure and fat oxidation thus preventing obesity and glucose intolerance. Importantly, estrogens improved metabolic homeostasis by increasing production of the hormone fibroblast growth factor 21 (FGF21). A pilot cross over study under the leadership of Dr. Ravussin will translate these findings in a small cohort of six postmenopausal women. We will investigate the effect of TSEC on basal metabolic rate, fat oxidation, body composition and systemic insulin action. In parallel, under the leadership of Dr. Mauvais-Jarvis, we will continue our basic investigation using our mouse model to test the hypothesis that TSEC enhance FGF21 sensitivity. 

INBRE Collaborative Projects

A Predictive Modeling Framework for Studying Disparity in Colorectal Screening
Prerna Dua, PhD, Louisianan Tech University
In collaboration with the LA CaTS Center Biomedical Informatics Core

This proposal aims to develop a colorectal cancer data repository by engaging participation from the Louisiana Clinical Data Research Network (LACDRN) from a regionally distributed population, and developing a predictive model by identifying the underlying key factors that are highly correlated with the gender and race. The proposed predictive model will then aid in computing the confidence associated with each patient on the risk of developing colon cancer. The results generated from the proposed study will lead us to advance in closing the loop between the established factors of race and gender as being the covariates, along with other unidentified and underlying environmental and socio-economic factors from South Louisiana.

Neurolymphatic Biomarker Analysis in Multiple Sclerosis
Urska Cvek, ScD, MBA, LSU Shreveport
J. Steven Alexander, PhD, LSUHSC Shreveport

Multiple sclerosis (MS) is a complex, devastating and enigmatic immune-mediated neurovascular disease of the central nervous system (CNS) that is characterized by inflammatory demyelination, degeneration of neurons and axonal loss. In our project we are proposing to examine endothelial particles that represent the future for analysis of blood biomarkers, as they can simultaneously provide information on several proteins originally derived from the brain cell surface. We would like to validate these biomarkers against the MRIs of the patients, which, until this time, have been the only objective and reliable diagnostic tool for MS. If our hypotheses are confirmed our project will propel the neurolymphatic biomarker matrix as a potentially new, non-invasive and inexpensive tool for diagnosis and monitoring of MS.

Other Pilot Projects

Community-Wide Health Assessment for West Carroll Parish (Community Pilot Project)
Peter Katzmarzyk, PhD, Pennington Biomedical Research Center, Principal Investigator

The objective of this project is to conduct a baseline health assessment of chronic disease, risk factors, and risk factor knowledge in West Carroll Parish. The community health assessment will include two components:

  1. A population health phone survey conducted by the LSU Public Policy Research Lab (address-based sample of 2,500 households; anticipate ~400 respondents), and
  2. Community health screenings (screening for CVD risk factors including obesity, hypertension, diabetes and dyslipidemia; 200 participants) conducted at the LSU/SU AgCenter Research and Extension Site in Oak Grove, Louisiana.

Establishing a Congenital Zika Virus Infection Model
Cindy A. Morris, Tulane University

The emergence of Zika virus (ZIKV) as a cause of birth defects represents a dramatic and imminent threat to maternal and child health. Through mechanisms that are undefined, ZIKV demonstrates the ability to cross the placenta, infect the developing fetus, and produce devastating neurological sequelae, including microcephaly. Since the infection can be transmitted by sexual contact in addition to mosquito bites, insect vector control alone may be insufficient to stem the epidemic, and women of reproductive age may be at risk even in temperate zones that do not harbor Aedes aegypti. The over-arching goal of this proposal is to develop a tractable animal (guinea pig) model system in which to study congenital ZIKV infection and to determine the susceptibility and permissiveness of the placenta to ZIKV infection toward the future goal of preclinical testing of immune-based therapies, vaccines, and antivirals aimed at preventing fetal transmission and attendant disease.

KCA Initiated Projects

*Projects initiated and supported by one or more of the LA CaTS Center Cores or Resources

Caregivers' Perceived Roles in Caring for Patients with Heart Failure: Implications for Healthcare Providers
Project initiated by Community Engagement & Outreach Resource
Betty Kennedy, PhD, Pennington Biomedical Research Center

Heart failure (HF) represents a momentous burden to patients and the healthcare system. More importantly, HF can be a huge burden for caregivers (usually family or friends), who play major roles in the lives of patients with HF. The purpose of this study was to determine what roles patients and caregivers perceive and desire for themselves, and to compare and contrast these roles with those they perceive to be desired by healthcare providers versus what providers perceive the roles of patients and caregivers are from their perspective. A total of 93 participants (60 patients, 22 caregivers, and 11 providers) were enrolled in the study. Patients and their caregivers individually participated in semi-structured interviews, and providers (cardiologists, nurses, medical assistants) participated in one of two structured focus groups. The major concerns and needs of HF patients causing them the most difficulty was limited ability to perform any activity due to shortness of breath and fatigue, while the uncertainty of HF and not knowing what is going to happen was the most difficult for caregivers. Providers in both structured focus groups regardless of rank order selected compliance with care, compliance with treatment plan, and compliance with medication as the top 3 issues likely to have the greatest impact, and education on the disease first (compliance with care) as the easiest strategy to implement for patients and their caregivers in the management of heart condition. Findings from this study suggest that caregiver interventions are warranted based on patients, caregivers, and providers perceptions.

Research Action for Health Network (REACHnet) Projects

*Collaborative projects between REACHnet and LA CaTS Biomedical Informatics and other Cores

The Incidence and Prevalence of Parkinson's disease: A Retrospective Study
Elizabeth Disbrow, PhD, LSU Health Sciences Center – Shreveport

Little is known about racial differences in the incidence and prevalence of Parkinson’s disease (PD). Data suggest racial differences in the onset and progression of PD; however studies are few and underpowered. The study aims are:

  1. To test the hypothesis that the incidence, prevalence and progression of PD differ across race.
  2. To estimate the degree to which the incidence, prevalence and progression of PD interact with racial differences in prevalence of co-morbidities.

In partnership with the LA CaTS Biomedical Informatics, Biostatistics and Health Literacy Cores we will design and implement a query of retrospective data from Louisiana including Parkinson’s disease severity, additional diagnoses, demographic data and insurance status. We will identify differences in incidence and prevalence rates in collaboration with LA CaTS statisticians (AIM 1), and perform mediation analysis to evaluate the degree to which comorbid conditions mediate the relationship between race and disease progression (AIM 2).

The Heart is the Matter: Building an Understanding of Congenital Heart Disease in Louisiana
Danielle Gottlieb-Sen, MS MD MPH, LSU Health Sciences Center-New Orleans

Across the United States, there is variability in congenital heart disease prevalence and outcomes. Understanding this variability requires investigation of the influences of genetics, environment, and health care delivery on the pathogenesis of disease and on the care of patients. For patients in Louisiana with congenital heart disease, the contribution of each of these factors remains undefined. The goal of this study is to better understand the epidemiology of congenital heart disease in Louisiana, and the patterns of prenatal care for patients with CHD in the state. Gaining an understanding of the epidemiology of congenital heart disease in Louisiana can focus effective health care delivery to this patient population.

The Landscape of End-of-Life Cancer Care in the Deep South
Michael Hoerger, PhD, MSCR, Tulane University

Louisiana has the 2nd highest cancer incidence rate and 4th highest cancer mortality rate in the country. Quality of life is crucial for patients who are dying of cancer. Receipt of more intense care in the final months of life hinders quality of life, both for patients and family caregivers. Leveraging REACHnet data of cancer decedents, this research will examine whether the intensity of end-of-life care differs depending on the patient’s race as well as comorbid health issues, such as cardiovascular disease, diabetes, obesity, smoking behaviors, and alcohol use. Findings will have implications for future research aimed at improving care and quality of life for patients with advanced cancer and their family caregivers.

Influenza infection in diabetic and elderly patients
Elizabeth B. Norton, MPH, PhD, Tulane University

The intent of applying to this Application is to (1) provide further support to ongoing research projects (specifically our recent LA CaTS pilot project “Vaccine efficacy in diabetic and elderly subjects”) and (2) clarify the role of seasonal influenza or flu infection on local diabetic populations using the REACHnet database. Diabetic patients are known to have complications with flu. However, except for rates of vaccination there is no published data on the incidence and complications from flu infection in regional diabetic patients. The objective of these studies is to perform a retrospective epidemiological analysis to define the burden of influenza infection on regional diabetic populations.