Role of Autophagy in Microglia-induced NeuroAIDS in Substance Abuse

描述（由申请人提供）：大约三分之一的HIV-1感染者发展为HIV-1相关的神经认知障碍（HAND）。 症状范围从轻微的困难到严重的神经退行性痴呆，甚至随着高效抗逆转录病毒疗法（HAART）的出现，虽然严重的艾滋病毒相关痴呆不太常见，但轻微的认知运动障碍仍然是感染的重要组成部分。阿片类药物的有害作用是复杂的，关于滥用药物对神经胶质细胞功能的作用的信息非常有限，尽管已知它们对阿片类药物反应至关重要。此外，药物滥用的作用和物质滥用对神经元功能的表现的后果并不为人所知。拟议的项目将调查自噬在药物滥用背景下小胶质细胞诱导的神经艾滋病中的作用。这三个相互关联的具体目标旨在：1）鉴定调节HIV-1复制的小胶质细胞生物学中的新机制，以及吗啡是否通过该途径会聚于HIV-1感染~ 2）在细胞水平表征HIV-1诱导的溶酶体功能障碍的后果，以及先前和/或同时的物质滥用是否改变细胞功能~ 3）检查信号通路和意义（保护与毒性）的自噬过程中激活的HIV-1和吗啡在小胶质细胞和神经元。 El-Hage博士拥有成功开展研究项目所需的专业知识、领导力和动力，获得该奖项的目的是使El-Hage博士成为一名独立的科学家。

DESCRIPTION (provided by applicant): Approximately one-third of HIV-1 infected individuals develop HIV-1-associated neurocognitive disorders (HAND). Symptoms range from minor difficulties to severe neurodegenerative dementia and even with the advent of highly active antiretroviral therapy (HAART), while severe HIV-associated dementia is less common, minor cognitive motor disorders remains an important part of infection. The deleterious effects of opiates are complex and information regarding the actions of drugs of abuse on glial cell function is very limited though they are known to be critical to opiate response. Moreover, the consequent effects of the actions of drugs of abuse and the manifestation of substance abuse on neuronal function are not well known. The proposed project will investigate the role of autophagy in microglia-induced neuroAIDS in the context of substance abuse. The three correlated specific aims are directed at: 1) identifying a novel mechanism in the biology of microglia that regulates HIV-1 replication and whether morphine converges on HIV-1 infection through this pathway~ 2) characterization at cellular levels the consequences of HIV-1 induced lysosomal dysfunction and whether prior and/ or concurrent substance abuse modifies cell function~ 3) examining the signaling pathways and the significance (protective vs. toxic) of the autophagy process activated by HIV-1 and morphine in microglia cells and neurons. Dr. El-Hage has the expertise, leadership, and motivation necessary to run a successful research program and the purpose of getting this award is to enable Dr. El-Hage to become an independent scientist.