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

基本信息

批准号：
9264742
负责人：
NAZIRA EL-HAGE
金额：
$ 3.77万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-10 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264742
关键词：
AIDS Dementia Complex Autophagocytosis Autophagosome Autopsy Award Biology Brain Breeding C57BL/6 Mouse CCR5 gene CXCR4 gene Cell physiology Cells Coculture Techniques Cognitive Complex Data Encephalitis Exposure to Functional disorder Goals HIV HIV-1 Health Highly Active Antiretroviral Therapy Homeostasis Human Image Implant Individual Infection Lead Leadership Life Lysosomes Microglia Minor Modeling Morphine Motivation Mus Nerve Degeneration 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 Virus Replication digital imaging drug of abuse gain of function genetic inducer imaging system inhibitor/antagonist insight loss of function mind control motor disorder neuroAIDS neurocognitive disorder neurodegenerative dementia neuron loss neurotropic new therapeutic target novel programs protein aggregate response

项目摘要

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 感染者会出现 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，即使出现了高效抗逆转录病毒疗法（HAART），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很复杂，尽管已知滥用药物对阿片类药物反应至关重要，但有关滥用药物对神经胶质细胞功能作用的信息非常有限。此外，滥用药物的作用和药物滥用的表现对神经元功能的后续影响尚不清楚。拟议的项目将研究自噬在药物滥用情况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针对：1) 确定小胶质细胞生物学中调节 HIV-1 复制的新机制，以及吗啡是否通过该途径集中于 HIV-1 感染~ 2) 在细胞水平上表征 HIV-1 的后果- 1 诱导的溶酶体功能障碍以及先前和/或同时的药物滥用是否会改变细胞功能~ 3) 检查信号通路以及 HIV-1 和吗啡激活的自噬过程的意义（保护性与毒性）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 博士成为一名独立科学家。