HIV Neural Apoptosis:Mechanisms, Pathways & Protection

HIV 神经细胞凋亡：机制、途径

• 批准号: 6872945
• 负责人: Dennis Larry Kolson
• 金额: $ 37.64万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6872945
• 关键词: AIDS /HIV neuropathy; AIDS dementia complex; BCL2 gene /protein; HIV envelope protein; apoptosis; biological signal transduction; gene expression; human immunodeficiency virus 1; human tissue; immunocytochemistry; laboratory rat; macrophage; neural degeneration; neuroprotectants; neurotoxins; protein kinase; western blottings

DESCRIPTION (provided by applicant): Neuronal apoptosis is a hallmark of AIDS dementia complex (ADC), and may represent a final common pathway of cell death in response to neurotoxins released from HIV-infected macrophages(HIV/MDM). Some forms of neuronal apoptosis are blocked by certain anti-apoptosis members of the bct-2gone family (Bcl-2 & Bcl-xL), which block the intrinsic (mitochondrial-associated) pathway. Neuronal apoptosis may also be blocked by activation of AKT/protein kinase B signaling (AKT/PKB), which acts at points involving the intrinsic and extrinsic (death receptor-associated) apoptosis pathways. How the intrinsic and/or extrinsic apoptosis pathways are involved in neuronal apoptosis in ADC is unknown, and this represents an important gap in our understanding of HIV neuropathogenesis and neuroprotective strategies. We have developed a novel in vitro model for HIV-induced neuronal apoptosis based on a unique human neuronal cell line (NT2.N). We found that Bcl-2 & Bcl-xL as well as activators of neuronal AKT/PKB block HIV/MDM-induced neuronal apoptosis. We have also demonstrated expression of the newly described seven-transmembrane HIV co-receptor APJ in neurons, and found that its native ligand, apelin, activates AKT/PKB and blocks such apoptosis. Finally, we have used a novel single-cell mRNA amplification technique to analyze gene expression in apoptotic neurons in vivo. Our hypothesis is that HIV induced neuronal apoptosis is mediated through specific pathways involving both intrinsic & extrinsic apoptosis mechanisms that may be differentially induced by HIV/MDM and HIV proteins, and that APJ activated signaling may modulate these pathways and mediate neuroprotective responses against effectors of HIV-associated apoptosis. Our aim is to better understand the pathways of HIV-induced neuronal apoptosis and the mechanisms of apelin/APJ neuroprotection, through our in vitro model and analysis of gene expression in apoptotic neurons in rive. We will: 1) Determine the pathways of neuronal apoptosis induced by HIV/MDM &: associated neurotoxins; 2) Define the neuroprotective signaling pathways for APJ/apelin against HIV/MDM; and 3) Determine the expression of genes modulating intrinsic & extrinsic apoptosis pathways and neuroprotective pathways in defined subclasses of apoptotic neurons in HIV-infected brain.

描述（由申请人提供）：神经细胞凋亡是艾滋病痴呆症（ADC）的一个标志，并且可能代表响应HIV感染的巨噬细胞（HIV/MDM）释放的神经毒素而导致细胞死亡的最终共同途径。 bct-2gone 家族（Bcl-2 和 Bcl-xL）的某些抗凋亡成员可阻断某些形式的神经元凋亡，从而阻断内在（线粒体相关）途径。 AKT/蛋白激酶 B 信号传导 (AKT/PKB) 的激活也可能阻断神经元凋亡，该信号作用于涉及内在和外在（死亡受体相关）凋亡途径的点。内在和/或外在凋亡途径如何参与 ADC 中的神经元凋亡尚不清楚，这代表了我们对 HIV 神经发病机制和神经保护策略的理解中的一个重要差距。我们基于独特的人类神经元细胞系（NT2.N）开发了一种新的 HIV 诱导神经元凋亡体外模型。我们发现 Bcl-2 和 Bcl-xL 以及神经元 AKT/PKB 激活剂可阻断 HIV/MDM 诱导的神经元凋亡。我们还证明了新描述的七次跨膜 HIV 共受体 APJ 在神经元中的表达，并发现其天然配体 apelin 激活 AKT/PKB 并阻止此类细胞凋亡。最后，我们使用了一种新型单细胞 mRNA 扩增技术来分析体内凋亡神经元的基因表达。我们的假设是，HIV 诱导的神经细胞凋亡是通过涉及内在和外在细胞凋亡机制的特定途径介导的，这些机制可能由 HIV/MDM 和 HIV 蛋白差异诱导，并且 APJ 激活的信号传导可能调节这些途径并介导针对 HIV 相关细胞凋亡效应物的神经保护反应。我们的目的是通过我们的体外模型和对 rive 凋亡神经元基因表达的分析，更好地了解 HIV 诱导的神经元凋亡途径和 apelin/APJ 神经保护机制。我们将： 1) 确定 HIV/MDM 和相关神经毒素诱导的神经细胞凋亡的途径； 2) 定义APJ/apelin对抗HIV/MDM的神经保护信号通路； 3)确定在HIV感染的大脑中的凋亡神经元的特定亚类中调节内在和外在凋亡途径以及神经保护途径的基因的表达。