巨噬细胞中E3泛素连接酶Cbl-b在心肌炎发生发展中的作用研究

项目名称： 巨噬细胞中E3泛素连接酶Cbl-b在心肌炎发生发展中的作用研究

项目编号： No.31500726

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 免疫学

项目作者： 赵伊遐

作者单位： 中南大学

项目金额： 22万元

中文摘要： 心肌炎是一种心肌炎症性疾病，是青少年心源性猝死的重要原因之一，与扩张性心肌病的发生密切相关。除病毒感染等直接损害心肌外，免疫反应损伤也在其发病过程中起重要作用。目前认为，心肌炎是一种CD4+ T细胞相关疾病，可能与Th17细胞介导的自身免疫反应有关。Cbl-b是调节免疫与耐受的关键调节因子之一，并可调节CD4+ T细胞的分化。以往研究中，我们发现Cbl-b可影响小鼠心肌Th17细胞应答及自身免疫性心肌炎的发生，但在体外，Cbl-b不直接调节Th17的分化，而调节Dectin-1通路诱导的巨噬细胞IL-6和TNF-α分泌。.本研究拟通过分析心肌炎患者及对照组Cbl-b表达及其临床资料，明确Cbl-b与心肌炎的关系。并通过动物、细胞和分子生物实验明确Cbl-b经何种途经调节巨噬细胞分泌细胞因子、进而影响Th17细胞或通过其他途经对心肌炎产生影响，从而对心肌炎的诊断和临床治疗新的靶点。

中文关键词： 自身免疫；T细胞；单核-巨噬细胞；疾病模型；其它自身免疫性疾病

英文摘要： Myocarditis is an acute inflammatory disease of the heart that may cause 5% to 20% of sudden death in young adults, and is the most common cause of dilated cardiomyopathy (DCM) in human. The injury of myocardium is due to the infection of viruses, and also the immunoreaction. . Casitas-B-lineage lymphoma-b (Cbl-b), an E3 ubiquitin ligase, negatively regulates T cell responses, and play a crucial in T cell tolerance. Cbl-b knockout mice are highly susceptible to experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) which are believed to be mediated by Th17. And experimental autoimmune myocarditis (EAM), an animal model of myocarditis, is also mediated by Th17 cells. However, although mice lacking Cbl-b develop severe myocarditis, surprisingly, Cbl-b deficiency in T cells is not the primary driving force for severe disease. Further analysis indicates that Cbl-b does not seem to inhibit Th17 cell differentiation. These data suggest that the severe myocarditis observed in Cbl-b knockout mice may not due to the loss of Cbl-b in T cells but rather in antigen presenting cells (APCs). In support of this notion, Dectin family degradation is compromised in macrophages, which then suppresses Th17 responses and susceptibility to EAM. In this proposal, we will investigate whether Cbl-b deficiency in macrophages results in severe myocarditis and heightened Th17 responses and myocarditis via targeting Dectin family of CLR for ubiquitination in macrophages. A better understanding of the cellular and molecular mechanisms involved in aberrant Th17 responses in EAM and possibly in subset of human myocarditis may provide a useful approach to develop novel strategies against a devastating heart disease.

英文关键词： autoimmune;T cell;monocyte/macrophage;Experimental autoimmune myocarditis;Myocarditis