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Round 10: 2021-2022 Pilot Projects

Sex Differences in COVID-19 Outcomes: Role of Sex Hormones, Inflammatory Biomarkers, Comorbidities, and Socio-demographic Factors

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

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

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

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

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

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

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

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.