自噬在HIV-1gp120致海马神经元损伤过程中的作用及信号机制研究

项目名称： 自噬在HIV-1gp120致海马神经元损伤过程中的作用及信号机制研究

项目编号： No.81471235

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 董军

作者单位： 暨南大学

项目金额： 70万元

中文摘要： 研究显示：因HAART治疗延长了艾滋病患者的生存期，40-60%的HIV感染者可出现HIV相关神经认知障碍(HAND)，其中起重要作用的包膜蛋白gp120在神经元损伤中的机制一直是研究的热点。本室及他人研究已证实gp120可致大鼠空间记忆障碍及海马神经元凋亡，近期我们观察自噬在gp120致大鼠海马神经元损伤过程中的变化，发现损伤早期自噬增强；晚期自噬过度增强伴神经元大量凋亡，但机制不清。此预实验结果显示自噬在gp120致神经元作用早期起保护作用，晚期自噬过度促凋亡。这种早、晚期截然不同的损伤差异可能通过各自不同的自噬信号转导通路实现。为验证此假说，本研究拟通过体内、外实验，采用形态学、行为学、分子生物学等技术，寻找自噬mTOR、非mTOR通路中的关键信号分子靶点并加以阻断，探究神经元早、晚期损伤中自噬水平的变化引起神经细胞凋亡变化的信号分子机制，为HAND的防治提供全新的视角和新策略。

中文关键词： HIV相关神经认知障碍；HIV-1；gp120；自噬；海马神经元；凋亡

英文摘要： HIV-associated neurocognitive disorders (HAND) are still an important problem in HIV-infected individuals despite the use of combination antiretroviral therapy (ART). HAND is present in 40 - 60% of HIV-infected individuals on ART. Although the exact mechanism by which HIV causes HAND remains unknown, HIV envelope glycoprotein gp120 likely plays an important role in the pathogenesis of HAND, as HIV gp120 is a potent neurotoxin. We and others have reported that HIV gp120 can induce apoptosis of neural cells in hippocampus and cause impairment of spatial learning and memory in Spraque Dawley (SD) rats. Significantly, our recent data demonstrated that autophagy markedly increased during the early stage of interaction between HIV gp120 and SD rat hippocampal neurons, while excessive autophagy accompaning with neuronal apoptosis was observed in the late stage of the interaction. Therefore, we hypothesize that neuronal autophagy increased in the early stage of interaction exerts a neuroprotective effect, and excessive autophagy in the late stage leads to neuronal apoptosis. We also hypothesize that autophagy triggers different signal pathways in the early stage versus the late stage. To test these hypotheses, we will use our established research approaches and techniques in morphological analysis, behavioral science, and molecular biology to disect gp120-triggered autophagy pathways. We will conduct in vitro and in vivo experiments to study key signal molecules that potentially link mTOR, non-mTOR and gp120-triggered autophagy pathways. Specific inhibitors of the key signal molecules will be used to probe their functions. Finally, we will study the molecular mechanisms undrlying neuronal autophagy and apoptosis in the early stage versus late stage of gp120 challenge. Our results will provide critical insights to the understanding of HAND pathogenesis and to the development of preventive and therapeutic interventions of HAND.

英文关键词： HIV-associated neurocognitive disorder;HIV-1 gp120;autophagy;hippocampal neuron;apoptosis