Chemokines and Viral-Induced Neurologic Disease

描述（由申请方提供）：本竞争性更新的长期目的是评价趋化因子和趋化因子受体在嗜神经性鼠冠状病毒（小鼠肝炎病毒（MHV））感染后神经系统疾病和修复中的功能作用。易感小鼠感染MHV可重复导致急性脑脊髓炎，随后发生慢性脱髓鞘疾病，其临床特征为上行性后肢麻痹，组织学特征为单核细胞浸润至中枢神经系统（CNS），伴有白色物质破坏。由于MHV诱导的脱髓鞘和人类脱髓鞘疾病多发性硬化症（MS）之间的临床和组织学疾病的相似性，MHV系统被认为是研究导致人类脱髓鞘疾病（如MS）的潜在病理机制的极好模型。与MS相似，T细胞和巨噬细胞被认为在导致白色物质破坏方面很重要。此外，趋化因子和趋化因子受体在MS患者以及MHV感染的小鼠的CNS内表达，表明在疾病的发病机制中具有突出作用。事实上，在之前的资助期间（2000年开始），我们已经确定了趋化因子和趋化因子受体在调节神经炎症中的功能作用，这些神经炎症通过调节淋巴细胞和巨噬细胞浸润参与宿主防御和脱髓鞘反应MHV感染。 目前的建议建立在我们以前的工作，并提供了机会，以确定趋化因子和趋化因子受体的功能作用，i）保护少突胶质细胞（中枢神经系统的髓鞘产生细胞）的损伤/死亡和ii）调节移植的神经祖细胞的生物学，如位置迁移和增殖，这有助于轴突髓鞘再生。 总之，这些研究将扩展我们目前对趋化因子及其受体如何参与保护和修复的理解。此外，从这些实验中获得的数据将确定用于治疗MS以及其他人类脱髓鞘疾病的潜在新治疗方法。

DESCRIPTION (provided by applicant): The long-term 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 an acute encephalomyelitis followed by a chronic demyelinating disease characterized clinically by ascending hind-limb paralysis and histologically by mononuclear cell infiltration into the central nervous system (CNS) 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 CNS of MS patients as well as MHV- infected mice indicating a prominent role in the pathogenesis of disease. Indeed, during the previous funding periods (initiated in 2000), we have defined functional roles for chemokines and chemokine receptors in regulating neuroinflammation that is involved in both host defense and demyelination in response to MHV infection by regulating lymphocyte and macrophage infiltration. The present proposal builds upon our previous work and offers the opportunity to define the functional role of chemokines and chemokine receptors in i) protecting oligodendrocytes (the myelin-producing cell of the CNS) from damage/death and ii) regulating the biology of engrafted neural progenitor cells e.g. positional migration and proliferation which contributes to axonal remyelination. Together, these studies will extend our current understanding of how chemokines and their receptors participate in protection and repair. Further, the data obtained from these experiments will identify potentially novel therapeutic approaches for treatment of MS as well as other human demyelinating diseases.