Chemokines and Viral-Induced Neurologic Disease

导致人类脱髓鞘疾病多发性硬化症（MS）的潜在病理机制知之甚少。目前的假设表明MS的病因是多因素的，包括个体的遗传背景以及环境影响，例如病毒。小鼠肝炎病毒（MHV，冠状病毒科的一种正链RNA病毒）感染易感小鼠可导致慢性脱髓鞘疾病。动物发生上行性后肢麻痹，伴有单核细胞浸润到CNS和髓鞘破坏。因此，脱髓鞘的MHV模型被认为是研究有助于MS患者脱髓鞘的免疫病理学机制的极好模型。T细胞和巨噬细胞是MS患者中MHV诱导的脱髓鞘以及脱髓鞘的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CNS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。这是特别相关的，因为最近的研究已经将趋化因子和趋化因子受体牵涉到MS的发病机制中。设计用于实现该目标的新策略包括i）使用抗趋化因子抗体，其特异性中和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（-/-）小鼠以评价CNS的MHV感染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滴注到小鼠的CNS中，以更好地理解这些分子在导致神经炎症和脱髓鞘。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CNS炎症和脱髓鞘的理解。最后，从这些实验中获得的数据可以确定潜在的目标，用于治疗性治疗的人MS。最后，从这些实验中获得的数据可以确定潜在的目标，用于治疗性治疗的人MS。最后，由于趋化因子已涉及许多炎症病理，从这些研究中获得的发现将与其他人类炎症性疾病。

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.