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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL077611-03S1
Application #
7286441
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Massicot-Fisher, Judith
Project Start
2004-07-01
Project End
2008-05-31
Budget Start
2006-09-01
Budget End
2007-05-31
Support Year
3
Fiscal Year
2006
Total Cost
$37,198
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Rose, Noel R (2016) Viral myocarditis. Curr Opin Rheumatol 28:383-9
Rose, Noel R (2015) Molecular mimicry and clonal deletion: A fresh look. J Theor Biol 375:71-6
Rose, Noel R (2011) The genetics of autoimmune thyroiditis: the first decade. J Autoimmun 37:88-94
Kaya, Ziya; Katus, Hugo A; Rose, Noel R (2010) Cardiac troponins and autoimmunity: their role in the pathogenesis of myocarditis and of heart failure. Clin Immunol 134:80-8
Baldeviano, G Christian; Barin, Jobert G; Talor, Monica V et al. (2010) Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy. Circ Res 106:1646-55
Rose, Noel R (2009) Myocarditis: infection versus autoimmunity. J Clin Immunol 29:730-7
Ligons, Davinna L; Guler, Mehmet L; Li, Haiyan S et al. (2009) A locus on chromosome 1 promotes susceptibility of experimental autoimmune myocarditis and lymphocyte cell death. Clin Immunol 130:74-82
Cihakova, Daniela; Rose, Noel R (2008) Pathogenesis of myocarditis and dilated cardiomyopathy. Adv Immunol 99:95-114
Cihakova, Daniela; Barin, Jobert G; Baldeviano, G Christian et al. (2008) L.E.A.P.S. heteroconjugate is able to prevent and treat experimental autoimmune myocarditis by altering trafficking of autoaggressive cells to the heart. Int Immunopharmacol 8:624-33
Li, Haiyan S; Ligons, Davinna L; Rose, Noel R et al. (2008) Genetic differences in bone marrow-derived lymphoid lineages control susceptibility to experimental autoimmune myocarditis. J Immunol 180:7480-4

Showing the most recent 10 out of 15 publications