权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

PROTECTING CNS CELLS FROM HIV AND HIV-INDUCED INJURY

保护中枢神经系统细胞免受艾滋病毒和艾滋病毒引起的损伤

基本信息

批准号：
6800556
负责人：
DAVID S STRAYER
金额：
$ 15.7万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-15 至 2006-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): In this R21 grant application, we propose here to study gene delivery to inhibit HIV replication and HIV toxicity for CNS cells. HIV encephalopathy is a common and potentially devastating complication of AIDS. Development of HW encephalopathy largely reflects HIV infection of brain cells, especially monocyte-derived macrophages (MDM) and microglia. It also may involve toxicity of certain HIV proteins for neurons. We will use gene delivery techniques to study inhibition of H1V infection and replication in primary cultured human MDM and microglia, and to examine protection of neurons from the ability of HIV gp120 envelope glycoprotein to induce apoptosis. Recombinant gene delivery vehicles derived from Talphag-deleted SV40 (rSV40s) permanently transduce unselected key CNS targets for HW, including microglia, neurons, and monocyte-derived macrophages (MDM) with >98% efficiency in vitro. We have found that HIV replicates in MDM and microglia, and that rSV40s carrying HIV inhibitory transgenes protect these cells from HIV replication. We have found as well that gp120 causes apoptosis in cultured neurons, and that rSV40 vectors that downregulate cell membrane CXCR4 or that provide antioxidant enzymes, such as catalase, protect these neurons. We propose to exploit these promising findings to study rSV40 gene delivery to protect the CNS cells from HIV. This proposal is based on the following hypothesis: To test this hypothesis, we propose the following specific aims: 1.) Identify optimal transgenes individually and in combination to inhibit HIV-1 in CNS cells. 2.) use gene delivery to protect NT2-derived neurons from apoptosis induced by HIV gene products. Despite the frequency and dire consequences of CNS HIV infection, people afflicted with HIV encephalopathy have few treatment options. We propose to address this therapeutic challenge using rSV40 gene delivery to the CNS, both to protect the brain from HIV infection and to mitigate HIV-induced CNS dysfunction.

描述(由申请人提供)：在这份R21拨款申请中，我们建议研究抑制HIV复制的基因传递和对CNS细胞的HIV毒性。HIV脑病是一种常见的、具有潜在破坏性的艾滋病并发症。HW脑病的发生在很大程度上反映了HIV对脑细胞，特别是单核细胞来源的巨噬细胞和小胶质细胞的感染。它还可能涉及某些HIV蛋白对神经元的毒性。我们将使用基因传递技术来研究在原代培养的人MDM和小胶质细胞中抑制H1V感染和复制的作用，并检查对HIV gp120包膜糖蛋白诱导细胞凋亡的神经元的保护作用。来自Talphag缺失的SV40(RSV40)的重组基因传递载体在体外以98%的效率永久性地转导未选择的针对HW的关键中枢神经系统靶点，包括小胶质细胞、神经元和单核细胞来源的巨噬细胞(MDM)。我们发现HIV在MDM和小胶质细胞中复制，携带HIV抑制转基因的rSV40保护这些细胞免受HIV复制。我们还发现gp120导致培养的神经元凋亡，而下调细胞膜CXCR4或提供抗氧化酶(如过氧化氢酶)的rSV40载体保护这些神经元。我们建议利用这些有希望的发现来研究rSV40基因传递以保护中枢神经系统细胞免受艾滋病毒感染。这一建议基于以下假设：为了检验这一假设，我们提出了以下具体目标：1)确定单独和联合使用最佳转基因以抑制中枢神经系统细胞中的HIV-1。2.)使用基因传递保护NT2来源的神经元免受HIV基因产物诱导的细胞凋亡。尽管CNS艾滋病毒感染的频率和可怕的后果，患有艾滋病毒脑病的人几乎没有治疗选择。我们建议通过将rSV40基因传递到中枢神经系统来解决这一治疗挑战，既可以保护大脑免受HIV感染，也可以缓解HIV诱导的中枢神经系统功能障碍。