Role of Autophagy in Microglia-induced NeuroAIDS in Substance Abuse

自噬在小胶质细胞诱导的药物滥用中的神经艾滋病中的作用

• 批准号: 8584593
• 负责人: NAZIRA EL-HAGE
• 金额: $ 38.13万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8584593
• 关键词: AIDS Dementia Complex; AIDS neuropathy; Autophagocytosis; Autophagosome; Autopsy; Award; Biology; Brain; Breeding; C57BL/6 Mouse; CCR5 gene; CXCR4 gene; Cell physiology; Cells; Coculture Techniques; Cognitive; Complex; Data; Dementia; Disease; Encephalitis; Exposure to; Functional disorder; Goals; HIV; HIV-1; Highly Active Antiretroviral Therapy; Homeostasis; Human; Image; Implant; Individual; Infection; Lead; Leadership; Life; Lysosomes; Microglia; Minor; Modeling; Morphine; Motivation; Mus; Nerve Degeneration; Neurocognitive; Neuroglia; Neurons; Neuropathogenesis; Opiates; Opioid; Organelles; Pathogenesis; Pathology; Pathway interactions; Persons; Placebo Control; Play; Population; Process; Proteins; Research; Role; Running; Sampling; Scientist; Signal Pathway; Signal Transduction; Staging; Substance abuse problem; Symptoms; System; Time; Tissues; Transfection; Transgenic Mice; Viral; digital imaging; drug of abuse; gain of function; genetic inducer; inhibitor/antagonist; insight; loss of function; mind control; motor disorder; neurodegenerative dementia; neuron loss; neurotropic; novel; programs; protein aggregate; public health relevance; response

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.

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，甚至随着高活性抗逆转录病毒疗法（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，药物滥用的作用和药物滥用对神经元功能的表现所产生的后果尚不清楚。拟议的项目将研究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。这三个相关的具体目标是：1)确定调节HIV-1复制的生物学新机制，以及吗啡是否通过这一途径聚集在HIV-1感染上；2)在细胞水平上表征HIV-1诱导的溶酶体功能障碍的后果，以及先前和/或同时滥用药物是否会改变细胞功能；3)检测小胶质细胞中HIV-1和吗啡激活的自噬过程的信号通路和意义（保护性与毒性）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，获得这个奖项的目的是使El-Hage博士成为一名独立的科学家。