Chemokines and Viral-Induced Neurologic Disease

这项竞争性更新的长期实验目标是评估 趋化因子及其受体在神经系统疾病和感染后修复中的作用 与一种嗜神经的小鼠冠状病毒，小鼠肝炎病毒(MHV)。易感小鼠感染猪瘟病毒 MHV可重复导致急性脑炎和慢性脱髓鞘疾病 临床上以后肢上行性瘫痪为特征，组织学上以单核细胞为特征 渗入中枢神经系统(CMS)并伴有脑白质破坏。由于 MHV诱导的脱髓鞘与人类在临床和组织学疾病上的相似性 脱髓鞘疾病多发性硬化症(MS)，MHV系统被认为是 以研究导致人类脱髓鞘疾病的潜在病理机制 如MS类似于MS，T细胞和巨噬细胞都被认为是导致 白质破坏。此外，趋化因子和趋化因子受体在 多发性硬化症患者和MHV感染的小鼠的CIM表明在促进炎症方面有作用。我们 已经成功地确定了大多数趋化因子和趋化因子受体具有性别抑制作用 在参与宿主防御和脱髓鞘反应中的重要和非冗余作用 MHV感染通过调节CMS内淋巴细胞和巨噬细胞的聚集来实现。 目前的建议试图了解T细胞 趋化因子CXCL10调节T细胞向CMS的渗透并影响 受损的中枢神经系统重新髓鞘形成。为此，实验将确定CXCL10是否有选择地招募 GD4+T细胞进入中枢神经系统并影响T细胞效应器功能。此外，研究将确定 HEW慢性CXCL10表达通过抑制中枢神经系统再髓鞘形成的能力 抑制少突胶质前体细胞所需的生长因子和趋化因子 在白质束内增殖和定位迁移，从而有助于重新髓鞘形成。 总之，这些研究将扩展我们目前对趋化因子及其受体如何 控制中枢神经系统炎症、脱髓鞘，并最终修复。此外，从这些数据中获得的数据 实验可能确定治疗多发性硬化症和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. "