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）：神经元凋亡是艾滋病痴呆症复合物（ADC）的标志，并且可能代表细胞死亡的最终常见途径，这是对来自HIV感染的巨噬细胞（HIV/MDM）的神经毒素的响应。某些形式的神经元凋亡被BCT-2GONE家族（BCL-2和BCL-XL）的某些抗凋亡成员阻塞，这些抗凋亡成员阻断了固有的（线粒体相关）途径。神经元凋亡也可能通过AKT/蛋白激酶B信号传导（AKT/PKB）的激活来阻止，该蛋白激酶B信号传导（AKT/PKB）在涉及固有和外在（死亡受体相关）凋亡途径的点上作用。在ADC中，固有和/或外在凋亡途径参与神经元凋亡是未知的，这代表了我们对HIV神经病发生和神经保护策略的理解的重要差距。我们已经开发了一种基于独特的人类神经元细胞系（NT2.N）的新型体外模型，用于HIV诱导的神经元细胞凋亡。我们发现BCL-2和BCL-XL以及神经元AKT/PKB障碍物HIV/MDM诱导的神经元细胞凋亡的激活剂。我们还证明了新描述的神经元中新描述的七跨膜HIV共受体APJ，并发现其天然配体Apelin激活了Akt/pKB并阻止了这种细胞凋亡。最后，我们使用了一种新型的单细胞mRNA扩增技术来分析体内凋亡神经元中的基因表达。我们的假设是，HIV诱导的神经元凋亡是通过涉及固有和外在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激活的信号可能会调节这些途径和介导神经保护性反应抗HIV与HIV与HIV伴随抗体的影响。我们的目的是通过我们的体外模型和RIVE中凋亡神经元中基因表达的分析，更好地了解HIV诱导的神经元凋亡的途径和丙蛋白/APJ神经保护的机制。我们将：1）确定HIV/MDM＆：相关神经毒素引起的神经元凋亡的途径； 2）定义APJ/APELIN针对HIV/MDM的神经保护信号通路； 3）确定调节hiv感染大脑中凋亡神经元定义的亚类中的内在和外在凋亡途径和神经保护途径的基因表达。