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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 对病毒感染或脑内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的发生有关，如艾滋病毒相关性痴呆(HAD)、阿尔茨海默病。促炎细胞因子肿瘤坏死因子和趋化因子单核细胞趋化蛋白-1的高表达通常与HAD和AIzheimer‘’S病的临床疾病有关。此外，遗传多态分析将肿瘤坏死因子和单核细胞趋化蛋白-1的高表达等位基因与HAD风险增加联系在一起。然而，这些蛋白在发病机制上的作用机制尚不清楚。此外，逆转录病毒感染后，TNF和MCP-1表达上调的原因尚不清楚。目前的建议将利用逆转录病毒感染的小鼠模型来分析肿瘤坏死因子和单核细胞趋化蛋白-1在神经系统疾病发病机制中的作用机制。基因敲除小鼠的研究表明，在该模型中，肿瘤坏死因子和单核细胞趋化蛋白-1的主要受体CCR2都与神经系统疾病有关。在这项建议中，我们将确定是否肿瘤坏死因子或CCR2的缺陷阻止了先天免疫反应的其他成分的激活，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)在诱导脑部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，但不是TLR3，被大脑中的神经毒力病毒感染上调。因此，TLR7通路的激活可能诱导与神经系统疾病相关的前炎性细胞因子/趋化因子反应。这些研究表明，促炎细胞因子和趋化因子如何参与非炎症性神经疾病，为抑制整个激活途径而不是试图阻断可溶的细胞因子或趋化因子开辟了潜在的治疗方法。

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.