Genetic mechanisms of autoimmune myocarditis

自身免疫性心肌炎的遗传机制

• 批准号: 7237204
• 负责人: Noel R. Rose
• 金额: $ 35.77万
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7237204
• 关键词: Age-Years; Apoptosis; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Backcrossings; Bone Marrow; Breeding; Cardiac Myosins; Cells; Chromosomes, Human, Pair 6; Code; Congenic Mice; Data; Dendritic Cells; Dexamethasone; Diabetes Mellitus; Disease model; Distal; Experimental Models; Foundations; Future; Genes; Genetic; Genetic Polymorphism; Genomics; Hematopoietic System; Homeostasis; Human; Immune; Immune system; Inbred NOD Mice; Lead; Leukocytes; Link; Lymphoid Cell; Measures; Modeling; Mus; Myeloid Cells; Myocarditis; Natural Killer Cells; Pathogenesis; Pattern; Phenotype; Predisposition; Protocols documentation; RNA Splicing; Relative (related person); Research Personnel; Resistance; Role; Rosa; Speed; Sudden Death; Susceptibility Gene; T-Lymphocyte; Testing; Tissues; Variant; Work; autoimmune thyroid disease; base; cell type; comparative; congenic; hematopoietic tissue; interest; macrophage; male; positional cloning; programs; research study; thymocyte

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]。与其他自身免疫性疾病一样，心肌炎发病的根本原因和机制尚不清楚。为了研究自身免疫性心肌炎和自身免疫性疾病的机制，我们建立了心肌肌球蛋白诱导的实验性自身免疫性心肌炎（EAM）小鼠模型[3]。该模型表明，心肌炎的易感性有很强的遗传影响，为了解这种自身免疫性疾病的发病机制提供了新的途径[8]。EAM模型是独特的，值得研究，除了其他自身免疫性疾病模型，因为它显示了更大的非H-2基因的影响，并显示了一个不寻常的男性的影响。在初步工作中，我们已经证明，小鼠染色体6和可能的1和4上的基因座参与易感性。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如糖尿病有关[7]。此外，Chr.1位点包括CTLA-4，一个免疫学上重要的基因，我们以前已经证明，调节心肌炎的发病机制。主要在男性中起作用的Chr.6基因座与在胸腺细胞稳态和凋亡中重要的基因座重叠[5]。我们建议最终建立的遗传学研究结果，这将是未来的定位克隆的基础，并进行功能研究的多态性CTLA-4可能会导致不同的易感性心肌炎。初步实验还表明，这些遗传位点通过造血组织发挥作用。我们建议巩固这些发现，并研究这些遗传位点通过免疫系统中的哪些特定细胞类型起作用。我们建立在我们的初步数据，提出假设驱动的目的，以确定控制易感性的宿主基因，并在自身免疫性心肌炎的小鼠模型中描述其作用机制。