Chemokines and Viral-Induced Neurologic Disease

描述(由申请人提供)：本次竞争性更新的长期目标是评估趋化因子和趋化因子受体在促进神经系统疾病和修复感染嗜神经的小鼠冠状病毒-小鼠肝炎病毒(MHV)中的功能作用。感染MHV易感小鼠可重复地导致急性脑脊髓炎和随后的慢性脱髓鞘疾病，其临床特征为上行性后肢瘫痪，组织学上表现为单个核细胞侵入中枢神经系统(CNS)并伴有白质破坏。由于MHV诱导的脱髓鞘疾病与人类多发性硬化症(MS)在临床和组织学上的相似之处，MHV系统被认为是研究人类脱髓鞘疾病(如MS)潜在病理机制的良好模型。与MS相似，T细胞和巨噬细胞在白质破坏中都被认为是重要的。此外，趋化因子和趋化因子受体在MS患者和MHV感染的小鼠的中枢神经系统中表达，表明在疾病的发病机制中起着重要作用。事实上，在之前的资助时期(始于2000年)，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，这些炎症涉及宿主防御和脱髓鞘反应，通过调节淋巴细胞和巨噬细胞的渗透来应对MHV感染。本研究建立在我们先前工作的基础上，并提供了机会来确定趋化因子和趋化因子受体在以下两个方面的功能作用：1)保护少突胶质细胞(中枢神经系统的髓鞘产生细胞)免受损伤/死亡；2)调节植入的神经前体细胞的生物学，例如促进轴突重新髓鞘形成的位置迁移和增殖。总之，这些研究将扩大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治疗多发性硬化症和其他人类脱髓鞘疾病的潜在新疗法。

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.