Chemokines and Viral-Induced Neurologic Disease

这种竞争性更新的长期实验目标是评估 趋化因子和趋化因子受体与神经系统疾病和感染后修复 与嗜神经性鼠冠状病毒，小鼠肝炎病毒（MHV）。易感小鼠感染 MHV可重复导致急性脑炎，随后是慢性脱髓鞘疾病 临床上以后肢上行性麻痹为特征，组织学上以单核细胞 浸润到中枢神经系统（CMS），伴有白色物质破坏。由于 MHV诱导的脱髓鞘和人类脱髓鞘之间临床和组织学疾病的相似性 脱髓鞘疾病多发性硬化症（MS），MHV系统被认为是治疗多发性硬化症的优秀模型。 研究人类脱髓鞘疾病的病理机制 与MS类似，T细胞和巨噬细胞都被认为在促进MS中是重要的。 白色物质破坏。此外，趋化因子和趋化因子受体在细胞内表达。 MS患者以及MHV感染小鼠的CIMS表明在促进炎症中的作用。我们 已经成功地确定了大多数趋化因子和趋化因子受体 在参与宿主防御和脱髓鞘反应中的重要和非冗余作用 通过调节CMS内的淋巴细胞和巨噬细胞积聚来控制MHV感染。 目前的建议旨在了解T细胞的潜在机制， 趋化因子CXCL10调节T细胞浸润到CMS中，并影响T细胞在CMS中的表达能力。 受损的中枢神经系统恢复髓鞘为此，实验将确定CXCL10是否选择性地招募 GD4 + T细胞进入CNS以及影响T细胞效应子功能。此外，研究将确定 新的慢性CXCL10表达通过以下途径抑制CNS经历髓鞘再生的能力： 抑制生长因子以及少突胶质细胞祖细胞所必需的趋化因子， 在白色物质束内增殖并定位迁移，从而有助于髓鞘再生。 总之，这些研究将扩展我们目前对趋化因子及其受体 控制CNS炎症、脱髓鞘，并最终修复。此外，从这些获得的数据 实验可以鉴定用于治疗患有MS的人以及其他疾病的潜在靶点。 炎症性疾病。 "

The long-term experimental objective of this competitive renewal is to evaluate the functional role of chemokine and chemokine receptors in contributing to neurologic disease and repair following infection with a neurotropic murine coronavirus, mouse hepatitis virus (MHV). Infection of susceptible mice with MHV reproducibly results in acute encephalitis followed by a chronic demyelinating disease characterized clinically by ascending hind-limb paralysis and histologically by mononuclear cell infiltration into the central nervous system (CMS) accompanied by white matter destruction. Due to the similarities in clinical and histologic disease between MHV-induced demyelination and the human demyelinating disease Multiple Sclerosis (MS), the MHV system is considered an excellent model in which to study the underlying pathological mechanisms contributing to human demyelinating diseases such as MS. Similar to MS, both T cells and macrophages are thought to be important in contributing to white matter destruction. In addition, chemokine and chemokine receptors are expressed within the CIMS of MS patients as well as MHV-infected mice suggesting a role in promoting inflammation. We have successfully determined that the majority of chemokines and chemokine receptorsexhibit important and non-redundant roles in participating in host defense and demyelination in response to MHV infection by regulating lymphocyte and macrophage accumulation within the CMS. The present proposal seeks to understand the underlying mechanisms by which the T cell chemoattractant CXCL10 modulates T cell infiltration into the CMS and influences the ability of the damaged CNS to remyelinate. To this end, experiments will determine if CXCL10 selectivelyrecruits GD4+ T cells into the CNS as well as influencing T cell effector functions. In addition, studies will define hew chronic CXCL10 expression suppresses the ability of the CNS to undergo remyelination through suppression of growth factors as well as chemokines necessary for oligodendrocyte progenitor cells to proliferate and positionally migrate within white matter tracts thus contributing to remyelination. Together, these studies will extend our current understanding of how chemokines and their receptors control CNS inflammation, demyelination, and ultimately repair. Further, the data obtained from these experiments may identify potential targets for therapeutic treatment of humans with MS as well as other inflammatory diseases. "