TNF AND MCP-1 IN RETROVIRUS-INDUCED BRAIN DISEASE

TNF 和 MCP-1 在逆转录病毒引起的脑部疾病中的作用

• 批准号: 6972197
• 负责人: Karin E Peterson
• 金额: $ 21.88万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6972197
• 关键词: AIDS dementia complex; Alzheimer' s disease; Retroviridae; Retroviridae disease; astrocytes; brain disorders; chemokine receptor; disease /disorder etiology; genetic strain; immune response; inflammation; laboratory mouse; microglia; monocyte chemoattractant protein 1; neuropathology; pathologic process; receptor expression; toll like receptor; tumor necrosis factor alpha; virus cytopathogenic effect; virus infection mechanism

The innate immune response to virus infection or protein aggregation in the brain has been implicated in the development of non-lymphocyte mediated neurological disorders such HIV-associated dementia (HAD), Alzheimer's disease. Increased expression of the proinflammatory cytokine TNFalpha and chemokine MCP-1 is often associated with clinical disease in HAD and AIzheimer's disease. Additionally, genetic polymorphism analysis linked high expression alleles of both TNFalpha and MCP-1 with increased risk for HAD. However, the mechanism by which these proteins contribute pathogenesis is not clear. Furthermore, it is unknown why TNFalpha and MCP-1 are upregulated in response to retrovirus infection. The current proposal will analyze the mechanism by which TNFalpha and MCP-1 contribute to neurological disease pathogenesis using a mouse model of retrovirus infection. Knockout mouse studies demonstrated that both TNFalpha and CCR2, the primary receptor for MCP-1, contribute to neurological disease in this model. In this proposal, we will determine if deficiency in either TNFalpha or CCR2 prevents the activation of other components of the innate immune response such as astrocyte or microglia activation and the induction of proinflammatory cytokine/chemokine responses. Additionally, we will also analyze the role of Toll-like receptors(TLR) in the induction of the cytokine/chemokine response to retrovirus infection in the brain. Initial studies indicate that TLR7, but not TLR3, is upregulated by neurovirulent virus infection in the brain. Thus, activation of the TLR7 pathway may induce the proinfiammatory cytokine/chemokine response associated with neurological disease. These studies how proinflammatory cytokines and chemokines are involved in non-inflammatory neurological diseases, leading the way for potential therapeutics that can inhibit entire pathways of activation, rather than trying to block soluble cytokines or chemokines.

对病毒感染或脑中蛋白质聚集的先天免疫应答已经涉及非淋巴细胞介导的神经系统疾病如HIV相关性痴呆（HAD）、阿尔茨海默病的发展。促炎细胞因子TNF α和趋化因子MCP-1的表达增加通常与HAD和阿尔茨海默病中的临床疾病相关。此外，遗传多态性分析将TNF α和MCP-1的高表达等位基因与HAD的风险增加联系起来。但 这些蛋白质参与发病的机制尚不清楚。此外，还不知道为什么TNF α和MCP-1在逆转录病毒感染时上调。目前的建议将使用逆转录病毒感染的小鼠模型分析TNF α和MCP-1促进神经系统疾病发病机制的机制。敲除小鼠研究表明，TNF α和CCR2（MCP-1的主要受体）均导致该模型中的神经系统疾病。在这个提议中，我们将确定TNF α或CCR2的缺乏是否会阻止先天免疫应答的其他组分的激活，例如星形胶质细胞或小胶质细胞的激活以及促炎细胞因子/趋化因子应答的诱导。此外，我们还将分析Toll样受体（TLR）在诱导细胞因子/趋化因子对脑中逆转录病毒感染的反应中的作用。最初的研究表明，TLR7，而不是TLR3，是上调神经毒性病毒感染的大脑。因此，TLR7途径的激活可诱导与神经系统疾病相关的促炎性细胞因子/趋化因子应答。这些研究如何促炎细胞因子和趋化因子参与非炎性神经系统疾病，为潜在的治疗方法，可以抑制整个途径， 激活，而不是试图阻止可溶性细胞因子或趋化因子。