Round 7: 2018-2019 Pilot Projects
Promoting Cardiovascular Health and Reducing Disparities with Native Americans
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
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
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
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
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
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, FSH40 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
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
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 10 g/L, with the highest value of 60 g/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.