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

摘要 这个Ruth L的目标。Kirschstein NRSA F31-多样性应用程序是为了加强博士前的培训， 年轻的酒精研究员这个奖学金机会也将为申请人提供研究培训 开展艾滋病毒/艾滋病相关的高优先级研究。申请人将获得进行研究的技能 集中在高度相关的慢性狂欢临床前模型中酒精介导的代谢功能障碍 酒精（CBA）和猴免疫缺陷病毒（SIV）感染。与艾滋病毒/艾滋病患者生活在一起的人中的危险酒精使用 艾滋病毒感染者（PLWH）几乎是普通人群的两倍。此外，慢性高危酒精使用和艾滋病毒/SIV都是 独立地与组织损伤相关，包括脂肪组织损伤。我们实验室以前的工作 使用SIV模型表明CBA施用降低了脂肪来源的干细胞的分化， 在ADSC中，脂肪细胞大小减少，胶原沉积和炎性细胞浸润增加， 无症状的雄性猕猴。然而，据我们所知，以前没有研究可以调查 CBA诱导的脂肪组织硬度对脂肪细胞代谢能力和功能的影响 SIV/HIV。科学文献中的报告和我们以前的研究支持中心假设，即CBA- 诱导的网膜脂肪组织（OmAT）僵硬是由细胞外基质（ECM）失调介导的 在SIV+恒河猴中促进脂肪细胞代谢失调的组合物。拟议的研究旨在 作为申请人培训计划的一部分，将采用综合方法评估以下内容 具体目的：1）检验CBA介导的OmAT促纤维化环境由以下不平衡引起的假设： SIV感染的猕猴中ECM的合成和降解，以及2）检验纤维化ECM 降低从SIV感染的猕猴中分离的ADSC的代谢能力。建议的调查结果 研究将提供一个更全面的了解脂肪组织功能障碍的背景下，SIV和 并将为未来的转化研究奠定基础。完成拟议的研究和 培训将促进申请人的进展，在酒精诱导的领域的独立研究人员 代谢失调

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.