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

抗逆转录病毒治疗影响星形胶质细胞的自噬，并可能导致艾滋病毒相关的神经认知障碍

• 批准号: 10477626
• 负责人: Laura Cheney
• 金额: $ 19.44万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10477626
• 关键词: Anti-Retroviral Agents; Astrocytes; Autophagocytosis; Autopsy; Brain; CRISPR/Cas technology; Cell physiology; Cells; Clinical; Communicable Diseases; Confocal Microscopy; Data; Development; Employment; Enzyme-Linked Immunosorbent Assay; Exposure to; Flow Cytometry; Foundations; Functional disorder; Genus Hippocampus; Glutamates; Goals; HIV; HIV Infections; HIV-associated neurocognitive disorder; Homeostasis; Human; Immunofluorescence Immunologic; Learning; Measures; Mediating; Medical center; Medicine; Membrane Potentials; Mentors; Microscopy; Mitochondria; Modeling; Neurodegenerative Disorders; Neuropathogenesis; Pathogenesis; Pathogenicity; Pathology; Persons; Pharmaceutical Preparations; Pharmacology; Plague; Principal Investigator; Process; Production; Program Development; Proteins; Proteolysis; Proteomics; Publishing; Quality Control; Quality of life; Quantitative Reverse Transcriptase PCR; RNA; Regimen; Reporter; Research; Respiration; Role; Specificity; Stimulus; Supporting Cell; Techniques; Tenofovir; Toxic effect; Transmission Electron Microscopy; Viremia; Western Blotting; Work; antiretroviral therapy; base; brain cell; brain tissue; career development; cell type; college; comorbidity; emtricitabine; experience; experimental study; extracellular; inhibition of autophagy; innovation; instructor; knock-down; light microscopy; mitochondrial autophagy; mortality; neuroAIDS; normal aging; novel; overexpression; prevent; receptor; response; skills; therapeutic target; therapy development; tool; uptake

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.

项目总结/摘要 该提案提出了一个为期4年的研究职业发展计划，重点是研究 在HIV相关神经认知障碍（HAND）的背景下， 对HAND发病机制的理解，目的是确定HAND治疗的靶点。的 候选人目前是Montefiore Medical的传染病和病理学讲师 中心/阿尔伯特·爱因斯坦医学院。该提案建立在候选人以前的艾滋病毒研究基础上， 通过整合两个新的专业领域的临床经验，由她的导师，伯曼博士和 博士Cuervo。拟议的实验和教学工作将为切尼博士提供技能， 她过渡到独立作为主要研究者在neuroHIV和macroautophagy的十字路口。 尽管用抗逆转录病毒药物控制了病毒血症，但仍有相当数量的HIV感染者（PWH）发展为HAND 治疗（ART）。对HAND的潜在因素的不完全理解阻碍了治疗HAND的努力。 发展数据表明，失调的自噬可能有助于HAND，但仍有很多工作要做。 特别是星形胶质细胞。维持星形胶质细胞的稳态是至关重要的，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。由于星形胶质细胞依赖于自噬 由于星形胶质细胞自噬的异常调节可能导致细胞内环境的改变，因此了解星形胶质细胞自噬的异常调节尤为重要， 手这一建议的基础是基于我们发表的数据，这些数据表明， 在原代人星形胶质细胞中的自噬，其由以下常用处方方案治疗引起： 替诺福韦、恩曲他滨和雷特格韦（ART）。本提案的目的是：1.描述ART诱导 人星形胶质细胞中自噬的变化，2.表征经处理的人星形胶质细胞中的选择性自噬 艺术，3。定义作为ART治疗结果的星形胶质细胞特异性功能的变化， 自噬的变化。这些目标将扩大对威尔斯亲王医院人力资源发展的理解， ART时代，最终目标是确定缓解HAND的治疗靶点。