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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 对病毒感染或脑中蛋白质聚集的先天免疫应答与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有关。促炎细胞因子TNF和趋化因子MCP-1的表达增加通常与HAD和阿尔茨海默病的临床疾病相关。此外，遗传多态性分析将TNF和MCP-1的高表达等位基因与HAD的风险增加联系起来。然而，这些蛋白质参与致病的机制尚不清楚。此外，还不清楚为什么TNF和MCP-1在逆转录病毒感染后上调。目前的建议将分析的机制，TNF和MCP-1有助于神经系统疾病的发病机制，使用逆转录病毒感染的小鼠模型。敲除小鼠研究表明，TNF和CCR 2（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或CCR 2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。初步研究表明， TLR 7，而不是TLR 3，在脑中被神经毒力病毒感染上调。因此，TLR 7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，导致潜在的治疗方法，可以抑制整个激活途径，而不是试图阻止可溶性细胞因子或趋化因子。

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 roinflammatory cytokine TNF 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 mechanismby which these proteins contribute pathogenesis is not clear. Furthermore, it is unknown why TNFand MCP-1 are upregulated in response to retrovirus infection. The current proposal will analyze the mechanism by which TNF 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.