Mechanisms by which effector T cells modulate endogenous remyelination

项目摘要： 该项目解决了一个重要的问题-多发性硬化症（MS），这是最常见的原因， 创伤后年轻人的神经功能障碍。虽然许多免疫疗法的批准已经 对减少复发缓解型MS中炎症性疾病活动的影响，迄今为止还没有治疗方法 增强髓磷脂的修复或显著影响疾病的进展阶段。虽然 非炎症机制可能导致进展性MS，最近的几篇论文强调了一个关键作用 在脑组织损伤部位或附近持续的炎症。T的直接致病作用 淋巴样脑膜滤泡的存在表明进行性MS中存在淋巴样细胞， 与皮质脱髓鞘和变薄有关。更详细地了解免疫细胞 抑制髓鞘再生对于开发增强髓鞘再生和阻止进行性MS治疗是关键的。 尽管观察证据表明免疫细胞可以抑制或促进 关于髓鞘再生，关于这些过程的具体机制知之甚少 发生.该项目解决了该领域进展的障碍，因为我们的理解 关于疾病中髓鞘再生失败的原因，目前还很有限，因为我们还没有阐明 少突胶质细胞前体细胞（OPC）分化失败的途径。我们计划追求一个令人兴奋的 新的观察结果表明，OPCs不仅不能分化成髓鞘产生细胞，而且在一个细胞中， 在炎症环境中，它们采用免疫表型（iOPC），并可以引发CD 8 T细胞， 并成为细胞毒性淋巴细胞（CTL）的靶点。这代表了思维模式的转变 OPC生物学和髓鞘再生的知识 我们将描述iOPC的特征、结局和功能。我们试图通过以下方式来理解这些机制： 它们激活CD 8 T细胞，进而杀死作为靶细胞的iOPC亚群。我们将跟踪iOPC使用 通过颅窗的命运映射策略和双光子活体显微镜。我们的目标是开发药物 靶向参与MHC表达的NFkB信号通路的治疗， 包括2型糖尿病药物依塞那肽和NLRX-1信号激动剂的方法 通常调节NF κ B表达的分子。

Project Summary: The project addresses an important problem - multiple sclerosis (MS), which is the most common cause of neurological disability in young adults after trauma. While the approval of numerous immunotherapies has had an impact on reducing inflammatory disease activity in relapsing remitting MS, there are no therapies to date that enhance repair of the myelin or markedly influence the progressive stage of the disease. Although non-inflammatory mechanisms may contribute to progressive MS, several recent papers highlight a critical role for ongoing inflammation within the brain at or next to sites of tissue injury. A direct pathogenic role for T cells in progressive MS has been suggested by the presence of lymphoid meningeal follicles, which are associated with cortical demyelination and thinning. A more detailed understanding of how immune cells inhibit remyelination is critical for developing therapies to enhance remyelination and halt progressive MS. Despite observational evidence that immune cells may suppress or promote remyelination, there is remarkably little known regarding the specific mechanisms by which these processes occur. This project addresses a barrier to progress in the field because our understanding of why remyelination fails in disease is presently limited because we have not elucidated the pathways involved in failed oligodendrocyte precursor cell (OPC) differentiation. We plan to pursue an exciting novel observation that not only do OPCs fail to differentiate into myelin producing cells, but in an inflammatory environment they adopt an immune phenotype (iOPCs) and can prime CD8 T cells, as well as become targets of the cytotoxic lymphocytes (CTL). This represents a paradigm shift in thinking about OPC biology and remyelination. We will characterize the profile, fate and function of iOPC. We seek to understand the mechanisms by which they activate CD8 T cells that in turn kill a subset of the iOPC as target cells. We will track iOPC using fate mapping strategies and two-photon intravital microscopy through cranial windows. We aim to develop drug therapies that target the NFkB signaling pathway involved in MHC expression using several novel therapeutic approaches including the type 2 diabetes mellitus drug exenatide and an agonist of the NLRX-1 signaling molecule that normally regulates NFkB expression.