TROY及其信号分子在多发性硬化症中的作用及机制研究

Multiple sclerosis (MS) is the most common type of the neuroimmunological diseases which is characterizaed by inflammatory demyelination of white matter in CNS. Microglia play key roles in pathologic process of MS. However,the effective therapy to control the MS is limited. In order to promote the novel therapeutic measurements,it need to strengthen the basic study on this disease.It has been reported that TROY receptor is broadly expressed in the brain.But the roles of which in the microglia remain elusive.In our preliminary data,we found that TROY was expressed in astrocytes and microglia of brain.The level of TROY in microglia of experimental autoimmune encephalomyelitis (EAE) models was significant higher than that in the control.The TROY expression was up-regulated by LPS stimulation in cultured microglia in vitro.Additionally,we also found that TROY interacted with several proteins, which had been reported as inflammation-related genes. Based on our interesting premilinary data, we plan to further detect the roles of TROY and its downstream signaling in the MS.To clarify the mechanism underlying these effects. To search the possibility to improve pathologic process of MS through intervene in TROY and the downstream signaling. We hope that our plan should not only deepen insight into the roles of TROY and its signaling in the MS but also provide clued to the potential clinical use.

多发性硬化症是最常见的神经免疫性疾病，以中枢神经系统白质炎性脱髓鞘病变为主要特点，小胶质细胞在其病变过程中扮演重要作用。目前，对其尚缺乏有效治疗手段。改善多发性硬化症诊疗现状需要大力加强相关基础研究。TROY受体在脑中有广泛表达，但它在小胶质细胞中所起的作用还很不清楚。我们在预实验研究中发现：TROY在脑中星形与小胶质细胞中有表达，在实验性脑炎小鼠脑小胶质细胞中表达水平显著提高；LPS刺激体外培养的小胶质细胞可以显著提高其中TROY表达；TROY还可以与多种炎症相关基因结合。本项目拟在已有工作基础上，深入发掘TROY及其信号通路在多发性硬化中的生物学作用，阐明介导这些效应的细胞和分子机制；探讨通过干预TROY及其信号通路改善多发性硬化症脑病过程的可能性。我们期望，这项研究能深化现有对TROY受体及其信号转导在多发性硬化症病变中作用的认识，并为潜在的临床应用提供理论和实践支持。

TROY在细胞存活、迁移和分化等多种功能活动中发挥作用。本研究中，我们发现LPS激活的体外培养的原代小胶质细胞以及EAE小鼠模型中TROY表达显著提高；TROY基因敲减后显著抑制小胶质细胞活化；将小胶质细胞中TROY表达基因敲减后可显著改善EAE小鼠病变过程；TROY/RKIP间存在生理性结合且TROY与RKIP间结合在EAE模型中显著增多；TAT-TROY (234-371aa)短肽可以有效穿膜进入小胶质细胞内并阻断TROY/RKIP间结合，腹腔注射TAT-TROY (234-371aa)短肽可以显著改善EAE模型小鼠发病；TROY基因敲减可以增强下游NF-kB活性，TAT-TROY(234-371aa)阻断TROY/RKIP结合后亦可以增强下游NF-kB活性。这项研究计划所得到的研究成果表明，TROY及其下游信号通路在包括脱髓鞘脑变性病、脑胶质瘤等疾病发展过程中扮演一定角色，是潜在的靶点，具有一定的科学意义。而研究数据和专利中可以阻断TROY/RKIP间结合的TAT-TROY(234-371aa)肽段可以显著改善疾病过程等关键数据，具有一定的应用前景。