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(申请人提供)：神经细胞凋亡是艾滋病痴呆复合体(ADC)的一个标志，并可能代表细胞死亡的最终共同途径，以应对艾滋病毒感染的巨噬细胞(HIV/MDM)释放的神经毒素。某些形式的神经细胞凋亡被BCT-2go家族的某些抗凋亡成员(Bct-2和Bclxl)阻断，从而阻断内在的(线粒体相关的)途径。AKT/蛋白激酶B信号通路(AKT/PKB)的激活也可以阻断神经元的凋亡，AKT/PKB信号通路作用于内源性和外源性(死亡受体相关)的凋亡通路。内源性和/或外源性凋亡通路如何参与ADC的神经细胞凋亡尚不清楚，这代表了我们对HIV神经发病机制和神经保护策略的理解的一个重要空白。我们以一种独特的人类神经细胞系(NT2.N)为基础，建立了一种新的HIV诱导神经细胞凋亡的体外模型。我们发现，Bcl2和Bclxl以及神经元AKT/PKB激活剂可阻断HIV/MDM诱导的神经细胞凋亡。我们还证明了新描述的七跨膜HIV共同受体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信使核糖核酸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诱导的神经细胞凋亡是通过特定的途径介导的，这些途径涉及HIV/MDM和HIV蛋白可能不同地诱导的内源性和外源性凋亡机制，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中凋亡神经元基因表达的分析，更好地了解HIV诱导神经元凋亡的途径和Apelin/APJ神经保护的机制。我们将：1)确定HIV/MDM诱导神经细胞凋亡的途径：相关的神经毒素；2)确定APJ/apelin抗HIV/MDM的神经保护信号通路；3)在HIV感染的脑内，确定调节内源性和外源性凋亡通路和神经保护通路的基因的表达。