Chemokines and Viral-Induced Neurologic Disease

导致人类脱髓鞘疾病多发性硬化症(MS)的潜在病理机制尚不清楚。目前的假说表明，MS的病因是多因素的，包括个体的遗传背景以及环境的影响，如病毒。易感小鼠感染小鼠肝炎病毒(MHV，冠状病毒科的一种正链RNA病毒)会导致慢性脱髓鞘疾病。动物出现上行性后肢瘫痪，并伴有单核细胞渗入中枢神经系统和髓鞘破坏。因此，MHV脱髓鞘模型被认为是研究MS患者脱髓鞘的免疫病理机制的良好模型。T细胞和巨噬细胞是MHV诱导的脱髓鞘和MS患者脱髓鞘发病机制的重要贡献者。这项研究计划的长期目标是更好地了解调节T细胞和巨噬细胞进入中枢神经系统的分子机制。为此，研究旨在评估趋化因子和趋化因子受体在MHV诱导的脱髓鞘发病机制中的作用。这一点尤其重要，因为最近的研究表明趋化因子和趋化因子受体参与了MS的发病机制。为实现这一目标而设计的新策略包括：i)使用抗趋化因子抗体特异性中和MHV感染小鼠体内的趋化因子活性，ii)利用趋化因子和趋化因子受体敲除(-/-)小鼠来评估MHV感染中枢神经系统后神经系统疾病的发展，以及iii)将表达重组小鼠趋化因子的复制缺陷型腺病毒载体注入小鼠的中枢神经系统，以更好地了解这些分子在神经炎症和脱髓鞘中的作用。总之，这些研究将扩大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和脱髓鞘的理解。此外，从这些实验获得的数据可能确定用于治疗多发性硬化症的人类的潜在靶点。最后，从这些实验获得的数据可能确定用于治疗多发性硬化症的潜在靶点。最后，由于趋化因子与许多炎症病理有关，从这些研究获得的结果将与其他人类炎症性疾病相关。

The underlying pathological mechanisms contributing to the human demyelinating disease Multiple Sclerosis (MS) are poorly understood. Current hypothesis indicate that the etiology of MS is multifactorial and includes the genetic background of the individual as well as environmental influences e.g. viral. Infection of susceptible mice with mouse hepatitis virus (MHV, a positive-strand RNA virus in the Coronaviridae family) results in a chronic demyelinating disease. Animals develop ascending hind-limb paralysis accompanied by mononuclear by mononuclear cell infiltration into the CNS and myelin destruction. As such, the MHV-model of demyelination is considered an excellent model to study the immunopathological mechanisms contributing to demyelination in patients with MS. T cells and macrophages are important contributors to the pathogenesis of MHV-induced demyelination as well as demyelination in MS patients. The long-range goal of this research proposal is to better understand the molecular mechanisms that regulate entry of T cells and macrophages into the CNS. To this end, studies are designed to evaluate the contributions of chemokines and chemokine receptors in the pathogenesis of MHV-induced demyelination. This is particularly relevant as recent studies have implicated chemokines and chemokine receptors in the pathogenesis of MS. Novel strategies designed to accomplish this goal include i) the use of anti-chemokine antibodies that specifically neutralize chemokine activity in vivo within MHV-infected mice, ii) utilization of chemokine and chemokine receptor knock-out (-/- ) mice to evaluate the development of neurologic disease following MHV infection of the CNS, and iii) the instillation of replication deficient adenovirus vectors that express recombinant mouse chemokines into the CNS of mice to better understand the contributions of these molecules in contributing to neuroinflammation and demyelination. Together, these studies will extend our current understanding of how chemokines and their receptors control CNS inflammation and demyelination. Further, the data obtained from these experiments may identify potential targets for therapeutic treatment of humans with MS. Finally, the data obtained from these experiments may identify potential targets for therapeutic treatment of humans with MS. Finally, as chemokines have been implicated in numerous inflammatory pathologies, findings obtained from these studies will be relevant to other human inflammatory diseases.