Antiretroviral Therapy Impacts Autophagy in Astrocytes, and May Contribute to HIV Associated Neurocognitive Disorders

项目摘要/摘要 这项建议提出了一个为期4年的研究职业发展计划，重点是研究 巨噬细胞(自噬)在HIV相关神经认知障碍(手)的背景下增加 了解手部的发病机制，以确定手部治疗的靶点。这个 候选人目前是Montefiore Medical的传染病和病理学讲师 中心/爱因斯坦医学院。该提案建立在候选人之前的艾滋病毒研究和 通过整合两个新的专业领域的临床经验，在她的导师伯曼博士和 库尔沃医生。拟议的实验和教学工作将为切尼博士提供技能集，使其能够 在神经艾滋病毒和巨细胞自噬的十字路口，她向独立的首席研究员的转变。 尽管使用抗逆转录病毒药物控制了病毒血症，但仍有相当数量的艾滋病毒携带者(PWH)出现手部症状 治疗(ART)。由于对其潜在因素的不完全了解，治疗手部疾病的努力受到阻碍。 发展。数据表明，失调的自噬可能会导致Hand，但还有很多事情要做 了解，特别是在星形胶质细胞中。维持星形胶质细胞的动态平衡至关重要，因为它们是主要的 支持大脑的细胞，为中枢神经系统执行许多重要功能。因为星形胶质细胞依赖于自噬 动态平衡，了解失调的星形胶质细胞自噬尤其重要，因为它可能有助于 手。这项建议的基础是我们公布的数据，证明了对 原代人类星形胶质细胞经常用处方方案处理后的自噬现象 替诺福韦、恩曲他滨和雷替格雷(第3条)。这项建议的目的是：1.描述诱导的ART 人脑星形胶质细胞自噬的变化，2.经处理的人脑星形胶质细胞选择性自噬的特征 定义ART治疗后星形胶质细胞特异性功能的变化，并与 伴随着自噬的变化。这些目标将扩大对威尔斯亲王医院手部发展的了解 艺术时代，最终目标是确定缓解手部症状的治疗靶点。

Project Summary/Abstract This proposal presents a 4 year research career development program focused on the study of macroautophagy (autophagy) in the context of HIV associated neurocognitive disorders (HAND) to increase the understanding of HAND pathogenesis with the goal of identifying targets for treatment of HAND. The candidate is currently an Instructor of Infectious Diseases and of Pathology at Montefiore Medical Center/Albert Einstein College of Medicine. The proposal builds on the candidate’s previous HIV research and clinical experiences by integrating two new domains of expertise, overseen by her mentors, Dr. Berman and Dr. Cuervo. The proposed experiments and didactic work will provide Dr. Cheney with the skill sets to enable her transition to independence as a Principal Investigator at the crossroads of neuroHIV and macroautophagy. A significant number of people with HIV (PWH) develop HAND despite control of viremia with antiretroviral therapy (ART). Efforts to treat HAND are hindered by an incomplete understanding of the factors underlying its development. Data suggest that dysregulated autophagy may contribute to HAND, but much remains to be understood, specifically in astrocytes. It is essential to maintain astrocyte homeostasis because they are major support cells of the brain, performing many vital functions for the CNS. As astrocytes rely on autophagy for homeostasis, it is particularly important to understand dysregulated astrocyte autophagy as it may contribute to HAND. The foundation for this proposal is based on our published data demonstrating an inhibitory effect on autophagy in primary human astrocytes resulting from treatment with a commonly prescribed regimen of Tenofovir, Emtricitabine and Raltegravir (ART). The aims of this proposal are to: 1. Characterize ART induced changes in autophagy in human astrocytes, 2. Characterize selective autophagy in human astrocytes treated with ART, and 3. Define changes in astrocyte-specific functions as a result of ART treatment, and correlate with changes in autophagy. These aims will expand the understanding of HAND development in PWH in the ART era, with the ultimate objective of identifying therapeutic targets with which to mitigate HAND.