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

摘要 Ruth L.Kirschstein NRSA F31-多样性申请的目标是加强博士前培训 年轻的未来酒精研究人员。这一奖学金机会也将为申请者提供研究培训。 需要进行与艾滋病毒/艾滋病有关的高度优先的研究。申请者将获得进行研究的技能 在高度相关的慢性狂欢临床前模型中集中于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。高危人群中的酒精使用情况 艾滋病毒(PLWH)几乎是普通人群的两倍。此外，长期高危饮酒和艾滋病毒/SIV都是 与组织损伤独立相关，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给药减少了脂肪来源干细胞的分化 (ADSC)，缩小脂肪细胞体积，增加胶原沉积和炎性细胞浸润 无症状的雄性猕猴。然而，据我们所知，之前没有任何研究可供调查 CBA诱导的脂肪组织僵硬对脂肪细胞代谢能力和功能的影响 SIV/HIV病毒。科学文献中的报告和我们之前的研究支持了CBA- 诱导的大网膜脂肪组织(Omat)僵硬是由细胞外基质(ECM)调节失调所介导的 促进SIV+猕猴脂肪细胞代谢失调的成分。建议进行的研究包括 作为申请者培训计划的一部分，将利用综合方法评估以下内容 具体目标：1)测试CBA介导的Omat促纤维化环境是由于 SIV感染猕猴细胞外基质的合成和降解2)检验纤维化细胞外基质的假说 降低从SIV感染的猕猴分离的ADSCs的代谢能力。建议的调查结果 研究将更全面地了解SIV和SIV背景下的脂肪组织功能障碍 并将为今后的翻译研究奠定基础。完成拟议的研究和 培训将促进申请者成为酒精诱导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.