Alcohol-induced skeletal muscle dysregulation in SIV/HIV: Mitochondrial-mediated mechanisms

项目总结/摘要 这个Ruth L的主要目的。Kirschstein NRSA F32申请是为了加强博士后的培养 一个有前途的年轻酒精研究人员，并提供研究培训所需的进行高优先级 艾滋病毒/艾滋病相关研究。申请人将获得进行基础和转化研究的技能，重点是 酒精介导的代谢并发症在艾滋病毒感染者（PLWH）中普遍存在， 支持由NIAAA艾滋病毒/艾滋病研究计划指定的高优先级研究领域。申请人 在应用运动生理学领域的人体酒精研究方面有着良好的记录， 她将结合基础临床前研究和最先进的分子技术， 酒精诱导的骨骼肌（SKM）线粒体失调的研究生态位。酒精使用风险 艾滋病毒/艾滋病感染者几乎是普通人群的两倍。慢性高危酒精使用和HIV/SIV是独立的 与包括SKM功能障碍在内的代谢合并症相关。我们实验室以前的工作使用了 猿猴模型表明，长期酗酒（CBA）管理降低氧化酶活性， 无症状雄性猕猴的最大耗氧率。初步数据显示已生成 结果表明，CBA降低了PGC-1β和TFAM的mRNA表达，TFAM是一种下游靶点， CBA给药、无症状、SIV+/ART+雌性恒河猴SKM中的PGC-1β。PGC-1β和TFAM 对线粒体的生物合成和体内平衡至关重要。然而，CBA诱导的功能变化， SKM线粒体和CBA降低SKM线粒体生物发生和功能的机制 艾滋病毒的背景尚不清楚。因此，所提出的工作的总体假设是，PGC降低- 1β是CBA介导的SIV+雌性恒河猴SKM线粒体生物发生和功能下降的基础 PGC-1β是改善线粒体稳态的潜在治疗靶点。我们也 假设处于危险中的酒精消耗降低了PLWH中SKM线粒体的生物发生和功能。 该假设将被系统地测试，具体目标如下：1）测试慢性病的假设， 酒精以PGC-1β依赖的方式降低成肌细胞的线粒体生物发生和功能， SIV+雌性恒河猴; 2）检验促进PGC-1表达的PGC-1蛋白表达将促进SIV+雌性恒河猴的PGC-1蛋白表达的假设。 SIV+雌性恒河猴成肌细胞线粒体生物发生和功能的补救性CBA介导的降低 猕猴;和3）建立从非人类灵长类动物的研究结果转化为PLWH与危险的酒精使用。 从拟议的应用程序产生的数据将提供更全面的分子理解， 线粒体功能障碍的背景下，艾滋病毒和酒精，并将提供一个基础，为未来的机制 和翻译研究。此外，完成拟议的研究和培训将支持申请人的 在酒精诱导的骨骼肌代谢领域的独立学术生涯的进展 PLWH中的失调。

Project Summary/Abstract The primary purpose of this Ruth L. Kirschstein NRSA F32 application is to enhance the postdoctoral training of a promising young alcohol researcher and to provide research training required to conduct High Priority HIV/AIDS-related research. The applicant will gain skills to conduct basic and translational research focused on alcohol-mediated metabolic complications prevalent among people living with HIV (PLWH), which directly supports a High Priority research area designated by the NIAAA Research Program on HIV/AIDS. The applicant has a strong track record of human subjects alcohol research in the field of applied exercise physiology, which she will integrate with basic preclinical research and state-of-the-art molecular techniques to develop her research niche in alcohol-induced skeletal muscle (SKM) mitochondrial dysregulation. At-risk alcohol use among PLWH is nearly twice that in the general population. Chronic at-risk alcohol use and HIV/SIV are independently associated with metabolic comorbidities including SKM dysfunction. Previous work from our laboratory using a simian model indicates that chronic binge alcohol (CBA) administration decreases oxidative enzyme activity and maximal oxygen consumption rate in asymptomatic male macaques. Preliminary data demonstrate generated for this application show that CBA reduces mRNA expression of PGC-1β and TFAM, a downstream target of PGC-1β, in SKM of CBA-administered, asymptomatic, SIV+/ART+ female rhesus macaques. PGC-1β and TFAM are essential for mitochondrial biogenesis and homeostasis. However, the CBA-induced functional changes in SKM mitochondria and the mechanism by which CBA reduces SKM mitochondrial biogenesis and function in the context of HIV is not known. Therefore, the global hypothesis of the proposed work is that decreased PGC- 1β underlies CBA-mediated decreases in mitochondrial biogenesis and function in SKM of SIV+ female rhesus macaques and that PGC-1β is a potential therapeutic target to improve mitochondrial homeostasis. We also hypothesize that at-risk alcohol consumption decreases SKM mitochondrial biogenesis and function in PLWH. The hypothesis will be systematically tested with the following specific aims: 1) Test the hypothesis that chronic alcohol decreases mitochondrial biogenesis and function in a PGC-1β dependent manner in myoblasts from SIV+ female rhesus macaques; 2) Test the hypothesis that pharmacologically promoting PGC-1 expression will rescue CBA-mediated decreases in mitochondrial biogenesis and function in myoblasts from SIV+ female rhesus macaques; and 3) Establish that findings from non-human primates translate to PLWH with at-risk alcohol use. Data generated from the proposed application will provide a more comprehensive molecular understanding of mitochondrial dysfunction in the context of HIV and alcohol and will provide a foundation for future mechanistic and translational studies. Additionally, completing the proposed research and training will support the applicant’s progression to an independent academic career in the field of alcohol-induced skeletal muscle metabolic dysregulation in PLWH.