HIV Neural Apoptosis:Mechanisms, Pathways & Protection

HIV 神经细胞凋亡：机制、途径

• 批准号: 6719629
• 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/6719629
• 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综合征（ADC）的标志，可能代表细胞死亡对HIV感染的巨噬细胞（HIV/MDM）释放的神经毒素的最终共同途径。某些形式的神经元凋亡被bct-2gone家族的某些抗凋亡成员（Bcl-2和Bcl-xL）阻断，其阻断内在（神经元相关）途径。神经元凋亡也可以通过激活AKT/蛋白激酶B信号传导（AKT/PKB）来阻断，其在涉及内在和外在（死亡受体相关）凋亡途径的点起作用。内源性和/或外源性凋亡途径如何参与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空白。我们已经开发了一种新的HIV诱导的神经元凋亡的体外模型的基础上，一个独特的人类神经元细胞系（NT2.N）。我们发现Bcl-2和Bcl-xL以及神经元AKT/PKB激活剂阻断HIV/MDM诱导的神经元凋亡。我们还证明了新描述的七跨膜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并阻断这种凋亡。最后，我们使用了一种新的单细胞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特定的途径介导的，涉及内在和外在的凋亡机制，可能是由HIV/MDM和HIV蛋白质差异诱导，并且APJ激活的信号可能调节这些途径，并介导针对HIV相关凋亡效应物的神经保护反应。我们的目的是更好地了解艾滋病病毒诱导的神经元凋亡的途径和apelin/APJ神经保护机制，通过我们的体外模型和基因表达的分析，在凋亡的神经元在rive。我们将：1）确定由HIV/MDM诱导的神经元凋亡的途径：相关的神经毒素; 2）定义APJ/apelin针对HIV/MDM的神经保护性信号传导途径;和3）确定调节HIV感染的脑中凋亡神经元的定义的亚类中的内在和外在凋亡途径和神经保护性途径的基因的表达。