Chronic binge alcohol in SIV infection: impact of adipose tissue stiffness on metabolic dysfunction

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ABSTRACT The goal of this Ruth L. Kirschstein NRSA F31-Diversity application is to enhance the predoctoral training of a young future alcohol researcher. This fellowship opportunity will also provide the applicant with research training required to conduct High Priority HIV/AIDS-related research. The applicant will achieve skills to conduct research concentrated on alcohol-mediated metabolic dysfunction in the highly relevant preclinical model of chronic binge alcohol (CBA) and simian immunodeficiency virus (SIV) infection. At-risk alcohol use among people living with HIV (PLWH) is nearly twice that of the general population. Also, chronic at-risk alcohol use and HIV/SIV are both independently associated with tissue injury, including adipose tissue injury. Previous work from our laboratory using a SIV model indicates that CBA administration decreases differentiation of adipose derived stem cells (ADSC), decreased adipocyte cell size and increases collagen deposition and inflammatory cell infiltration in asymptomatic male macaques. However, to our knowledge, there have been no previous studies to investigate the impact of CBA-induced adipose tissue stiffness on adipocyte metabolic capacity and function in the context of SIV/HIV. Reports in the scientific literature and our previous studies support the central hypothesis that CBA- induced omental adipose tissue (OmAT) stiffness is mediated by dysregulation of extracellular matrix (ECM) composition promoting adipocyte metabolic dysregulation in SIV+ rhesus macaques. The proposed studies to be performed as part of the applicant’s training plan will utilize an integrated approach to assess the following Specific Aims: 1) Test the hypothesis that CBA-mediated OmAT pro-fibrotic milieu results from an imbalance in ECM synthesis and degradation in SIV-infected macaques and 2) Test the hypothesis that fibrotic ECM decreases metabolic capacity of ADSCs isolated from SIV-infected macaques. Findings from the proposed studies will provide a more comprehensive understanding adipose tissue dysfunction in the context of SIV and alcohol and will provide the foundation for future translational studies. Completion of the proposed research and training will facilitate the applicant’s progression to an independent researcher in the field of alcohol-induced metabolic dysregulation.