This program of research is designed to address the critical need for greater understanding of the genetic basis and electrophysiological mechanisms of Ca2+ triggered arrhythmias in inherited diseases and syndromes such as CPVT, LQTS, and HCM as a means to better understand the pathogenesis of sudden cardiac arrest in these populations. Specific objectives are to determine (1) the genetic basis for increased susceptibility to triggered arrhythmias, including the causative and modifier roles played by mutations or polymorphisms in ion channels, the intracellular Ca2+ release channel, and associated proteins, (2) the electrophysiological basis for triggered arrhythmias arising from a diverse range of mutations in ion channels, the Ca release channel, or myofibrillar proteins expressed in murine models, and (3) whether triggered arrhythmias arising from different primary causes ultimately involve a common cellular mechanism that gives rise to aberrant electrical activity in the cell and sudden cardiac arrest. The program is comprised of four sub-projects and four cores. Subproject 1 will determine the functional consequences of novel RYR2 mutations, including a common polymorphism in RyR2, and the mechanisms by which the molecular phenotype causes the clinical phenotype of CPVT. Subproject 2 will investigate the novel observation of KCNJ2 mutations in CPVT and determine the mechanisms by which these mutations current cause CPVT. Subproject 3 will use knock-in models of HCM to determine the mechanisms for Ca2+-triggered arrhythmia and determinants of risk for arrhythmias in this disease. Subproject 4 will pursue novel mutations in known genes, as well as novel gene candidates for CPVT and also in a cohort of HC patients, to test the idea that functional polymorphisms in genes related to CPVT may predispose some HCM patients to triggered arrhythmias. Scientific cores are focused on (Core B) genotyping of patient cohorts exhibiting sudden cardiac arrest and/or hypertrophic cardiomyopathy, (Core C) molecular biology and development of animal models of cardiac disease, and (Core D) in vivo functional characterization of mouse lines developed in the subprojects. The cores will provide support to the sub-projects and will facilitate development of new research directions. Our uniquely complementary approaches will yield new information concerning genetic and sub-cellular processes that confer increased risk for sudden cardiac arrest in heritable cardiac diseases in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL094291-05
Application #
8509771
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Boineau, Robin
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$1,905,133
Indirect Cost
$495,079
Name
University of Wisconsin Madison
Department
Physiology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Escobar, Ariel L; Valdivia, Héctor H (2014) Cardiac alternans and ventricular fibrillation: a bad case of ryanodine receptors reneging on their duty. Circ Res 114:1369-71
Kalscheur, Matthew M; Vaidyanathan, Ravi; Orland, Kate M et al. (2014) KCNJ2 mutation causes an adrenergic-dependent rectification abnormality with calcium sensitivity and ventricular arrhythmia. Heart Rhythm 11:885-94
Zhao, Yan-Ting; Valdivia, Héctor H (2014) Ca2+ nanosparks: shining light on the dyadic cleft but missing the intensity of its signal. Circ Res 114:396-8
Loaiza, Randall; Benkusky, Nancy A; Powers, Patricia P et al. (2013) Heterogeneity of ryanodine receptor dysfunction in a mouse model of catecholaminergic polymorphic ventricular tachycardia. Circ Res 112:298-308
Wooten, Eric C; Hebl, Virginia B; Wolf, Matthew J et al. (2013) Formin homology 2 domain containing 3 variants associated with hypertrophic cardiomyopathy. Circ Cardiovasc Genet 6:10-8
Reynolds, Julia O; Chiang, David Y; Wang, Wei et al. (2013) Junctophilin-2 is necessary for T-tubule maturation during mouse heart development. Cardiovasc Res 100:44-53
Landstrom, A P; Ackerman, M J (2012) Beyond the cardiac myofilament: hypertrophic cardiomyopathy- associated mutations in genes that encode calcium-handling proteins. Curr Mol Med 12:507-18
Giudicessi, John R; Ackerman, Michael J (2012) Potassium-channel mutations and cardiac arrhythmias--diagnosis and therapy. Nat Rev Cardiol 9:319-32
Ullrich, Nina D; Valdivia, Hector H; Niggli, Ernst (2012) PKA phosphorylation of cardiac ryanodine receptor modulates SR luminal Ca2+ sensitivity. J Mol Cell Cardiol 53:33-42
Bos, J Martijn; Subramaniam, Malayannan; Hawse, John R et al. (2012) TGF?-inducible early gene-1 (TIEG1) mutations in hypertrophic cardiomyopathy. J Cell Biochem 113:1896-903

Showing the most recent 10 out of 22 publications