Genetic mechanisms of autoimmune myocarditis

自身免疫性心肌炎的遗传机制

• 批准号: 7286441
• 负责人: Noel R. Rose
• 金额: $ 3.72万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7286441
• 关键词: CD28 molecule; NOD mouse; autoimmune disorder; cell type; chromosome aberrations; gene mutation; genetic markers; genetic polymorphism; genetic susceptibility; genetically modified animals; laboratory mouse; linkage mapping; molecular cloning; myocarditis; nucleic acid sequence; pathologic process; polymerase chain reaction; statistics /biometry

DESCRIPTION (provided by applicant): Myocarditis is a major cause of sudden death in people under 40 years of age, and many of these cases are associated with an autoimmune process[1, 2]. Like other autoimmune diseases, the fundamental causes and mechanisms of pathogenesis of myocarditis are not understood. To study the mechanisms of autoimmune myocarditis and autoimmune diseases in general we have developed a murine model of experimental autoimmune myocarditis (EAM) induced by cardiac myosin [3]. This model demonstrates that there are strong genetic influences to susceptibility to myocarditis, offering a fresh avenue into understanding the pathogenesis of this autoimmune disease [8]. The EAM model is unique and worthy of study apart from other autoimmune disease models because it shows greater influence of non H-2 genes, and shows an unusual male influence. In preliminary work we have demonstrated that loci on murine chromosomes 6 and possibly 1 and 4 are involved in susceptibility. Two of these loci (Chr. 1, Chr.6) interact and are also implicated in other autoimmune disease such as diabetes [7]. Furthermore, the Chr. 1 locus includes CTLA-4, an immunologically important gene, which we have previously demonstrated to regulate the pathogenesis of imyocarditis. The Chr.6 locus, which functions primarily in males, overlaps with loci that are important in thymocyte homeostasis and apoptosis [5]. We propose to conclusively establish the genetic findings which will be the foundation of future positional cloning and perform functional studies of polymorphisms in CTLA-4 which may lead to differential susceptibility to myocarditis. Preliminary experiments also indicate that these genetic loci act through hematopoietic tissues. We propose to solidify these findings and investigate through which specific cell types in the immune system these genetic loci operate. We build on our preliminary data to propose hypothesis-driven aims to identify host genes that control susceptibility and characterize their mechanisms of action in a murine model of autoimmune myocarditis.

描述（由申请人提供）：心肌炎是40岁以下人群猝死的主要原因，其中许多病例与自身免疫过程有关[1，2]。像其他自身免疫性疾病一样，心肌炎发病机理的基本原因和机制尚不清楚。为了研究心脏肌球蛋白诱导的实验性自身免疫性心肌炎（EAM）的鼠类自身免疫性心肌炎和自身免疫性疾病的机制[3]。该模型表明，对心肌炎的易感性有很大的遗传影响，为了解这种自身免疫性疾病的发病机理提供了新的途径[8]。除其他自身免疫性疾病模型外，EAM模型是独特的，值得研究，因为它显示出非H-2基因的影响更大，并且显示出异常的男性影响。在初步工作中，我们证明了鼠染色体6，可能1和4的基因座涉及易感性。这些基因座中的两个（Chr。1，Chr.6）相互作用，也与其他自身免疫性疾病（例如糖尿病）有关[7]。此外，Chr。 1基因座包括CTLA-4，一种是一种免疫学上重要的基因，我们先前已证明它可以调节膜炎的发病机理。 Chr.6基因座主要在雄性中起作用，与胸腺细胞稳态和凋亡非常重要的基因座重叠[5]。我们建议最终建立遗传发现，这将是未来位置克隆的基础，并对CTLA-4中多态性进行功能研究，这可能导致对心肌炎的敏感性不同。初步实验还表明，这些遗传基因座通过造血组织起作用。我们建议巩固这些发现并研究这些遗传基因座的免疫系统中哪些特定细胞类型。我们以初步数据为基础，以提出假设驱动的目的，以识别控制敏感性并在鼠自身免疫性心肌炎模型中表征其作用机理的宿主基因。