LSU VETERINARY COBRE: TNF & MCP-1 IN RETROVIRUS INDUCED BRAIN DISEASE

路易斯安那州立大学兽医 COBRE：TNF

• 批准号: 7382144
• 负责人: Karin E Peterson
• 金额: $ 16.42万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382144
• 关键词: LSU; VETERINARY; COBRE; TNF; MCP

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 TNFo_ 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 TNF_ 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 TNF_ and MCP-1 are upregulated in response to retrovirus infection. The current proposal will analyze the mechanism by which TNFa and MCP-lcontribute to neurological disease pathogenesis using a mouse model of retrovirus infection. Knockout mouse studies demonstrated that both TNF_ 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 TNF_ 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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。对病毒感染或大脑中蛋白质聚集的先天免疫反应与非淋巴细胞介导的神经系统疾病（例如 HIV 相关痴呆 (HAD)、阿尔茨海默氏病）的发生有关。促炎细胞因子TNFα和趋化因子MCP-1表达的增加通常与HAD和阿尔茨海默氏病的临床疾病相关。此外，遗传多态性分析将 TNF_ 和 MCP-1 的高表达等位基因与 HAD 风险增加联系起来。然而，这些蛋白质促进发病机制的机制尚不清楚。此外，尚不清楚为什么 TNF_ 和 MCP-1 因逆转录病毒感染而上调。目前的提案将使用逆转录病毒感染的小鼠模型来分析 TNFa 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_ 和 CCR2（MCP-1 的主要受体）均导致该模型中的神经系统疾病。在本提案中，我们将确定 TNF_ 或 CCR2 的缺陷是否会阻止先天免疫反应其他成分的激活，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/趋化因子反应的诱导。此外，我们还将分析 Toll 样受体 (TLR) 在诱导大脑中逆转录病毒感染的细胞因子/趋化因子反应中的作用。初步研究表明，TLR7（而非 TLR3）会因大脑中的神经毒力病毒感染而上调。因此，TLR7 通路的激活可能诱导与神经系统疾病相关的促炎性细胞因子/趋化因子反应。这些研究促炎性细胞因子和趋化因子如何参与非炎性神经系统疾病，为抑制整个激活途径的潜在治疗方法开辟了道路，而不是试图阻断可溶性细胞因子或趋化因子。