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Round 6: 2017-2018 Pilot Projects

Biological Predictors of Poor Surgical Outcomes Associated with Total Knee Arthroplasty

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

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

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 

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 

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

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

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

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

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.