Chemokines and Viral-Induced Neurologic Disease

摘要 这项研究计划的长期目标是关注趋化因子的功能作用， 趋化因子受体在两种已建立的CNS疾病模型中的疾病、保护和修复作用： 用嗜神经性小鼠肝炎病毒（JHMV）JHM株感染易感小鼠， 自身免疫性脑脊髓炎（EAE）。在这两种模型中，疾病的特征是持续的脱髓鞘 由炎性T细胞和巨噬细胞介导，在临床和组织学上与 人类脱髓鞘疾病多发性硬化症（MS）。具体而言，此修订后的应用程序将定义 趋化因子CXCL1及其信号受体CXCR2影响神经炎症、脱髓鞘和 在神经炎症和脱髓鞘的JHMV和EAE模型中的髓鞘再生。为了做到这一点，我们 i）星形胶质细胞衍生的趋化因子CXCL 1的表达是可诱导的 在多西环素（Dox）治疗后，和ii）CXCL 1的信号传导受体CXCR 2被选择性消融， 他莫昔芬（4-OHT）治疗后，在成年小鼠少突胶质细胞。我们将利用这些动物 已发表的数据和广泛的初步数据，以进一步确定CXCL1如何通过吸引 嗜中性粒细胞进入CNS以及影响OPC成熟。同样，我们将描述如何针对 少突胶质细胞上CXCR2的消融影响神经炎症和髓鞘再生。从这些 研究将进一步阐明CXCL1：CXCR2信号轴在这两种疾病中的重要性， 并可能揭示这些是治疗人类脱髓鞘的相关靶点 疾病如MS。

ABSTRACT The long-term objective of this research proposal is to focus on the functional role of chemokines and chemokine receptors in disease, protection, and repair in two well-established models of CNS disease: infection of susceptible mice with the neurotropic JHM strain of mouse hepatitis virus (JHMV) and experimental autoimmune encephalomyelitis (EAE). In both models, disease is characterized by ongoing demyelination mediated by inflammatory T cells and macrophages that is similar both clinically and histologically with the human demyelinating disease multiple sclerosis (MS). Specifically, this revised application will define how the chemokine CXCL1 as well as it’s signaling receptor CXCR2 affects neuroinflammation, demyelination and remyelination in the JHMV and EAE models of neuroinflammation and demyelination. To accomplish this, we will use mice engineered in which i) astrocyte-derived expression of the chemokine CXCL1 is inducible following doxycycline (Dox) treatment and ii) CXCR2, a signaling receptor for CXCL1, is selectively ablated upon tamoxifen (4-OHT) treatment within oligodendroglia in adult mice. We will use these animals to build on both published data and extensive preliminary data to further define how CXCL1 affects disease by attracting neutrophils into the CNS as well as influencing OPC maturation. Similarly, we will characterize how targeted ablation of CXCR2 on oligodendrocytes affects neuroinflammation and remyelination. Results from these studies will provide additional clarity to the importance of the CXCL1:CXCR2 signaling axis in both disease progression and repair and may reveal these to be relevant targets for treatment of human demyelinating diseases such as MS.