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和 趋化因子受体在两种公认的中枢神经系统疾病模型中的疾病、保护和修复： 嗜神经性小鼠肝炎病毒JHM株感染易感小鼠的实验研究 自身免疫性脑脊髓炎(EAE)。在这两种模型中，疾病的特征都是持续脱髓鞘。 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(MS)。具体地说，这个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 神经炎症和脱髓鞘的JHMV和EAE模型中的重新髓鞘形成。为了实现这一目标，我们 将使用这样的小鼠：1)星形胶质细胞衍生的趋化因子CXCL1的表达是可诱导的 在多西环素(Dox)治疗和II)CXCL1的信号受体CXCR2被选择性地消融后 用他莫昔芬(4-OHT)治疗成年小鼠的少突胶质细胞。我们将利用这些动物在 已发表的数据和大量的初步数据进一步定义了CXCL1如何通过吸引 中性粒细胞进入中枢神经系统并影响OPC的成熟。同样，我们将描述如何有针对性 去除少突胶质细胞上的CXCR2会影响神经炎症和重新髓鞘形成。来自这些的结果 研究将进一步阐明CXCL1：CXCR2信号轴在这两种疾病中的重要性 进展和修复，并可能揭示这些可能是治疗人类脱髓鞘的相关靶点 多发性硬化症等疾病。

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.