Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited disease characterized by progressive replacement of right ventricular myocardium with fibrous and adipose tissue. Key features of ARVC are frequent ventricular arrhythmias and a high propensity to sudden cardiac death (SCO), in the absence of evident ventricular dysfunction. Several cases of ARVC have been linked to mutations in desmosomal proteins. The question arises as to the mechanism by which desmosomal mutations lead to severe ventricular rhythm disturbances. It is the long-term goal of this project to characterize the molecular and functional events that link ARVC-relevant mutations in desmosomal proteins to ventricular arrhythmias and SCO. Here, we collaborate with investigators in Project 3 to test the general hypothesis that ARVC- relevant mutations lead to the disruption of gap junction-mediated electrical communication between cells. Our experiments center, for the most part, on the desmosomal protein plakophilin-2 (PKP2) and the effect that mutations or loss of this protein has on the integrity of the intercalated disc. These studies are largely motivated by genetic analysis showing that several cases of ARVC are linked to PKP2 mutations, and by cardiac pathology studies (including our preliminary data) showing marked decrease of gap junction plaques in hearts of patients expressing mutated desmosomal proteins. Specifically, we will: 1) Identify the structural determinants of the PKP2-desmoplakin interaction, and their modification by ARVC relevant mutations, 2) characterize the effects that modifications in PKP2 have on the structure of the intercalated disc and on the function of cardiac gap junctions, and 3) characterize the structural and biochemical composition of the intercalated disc in a canine model of inherited ARVC. Together with Project 3 as well as Cores B and C, we will provide an integrated description of the pathophysiology of ARVC, from the molecule to the entire heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL087226-05
Application #
8374506
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2013-07-31
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$368,197
Indirect Cost
$126,775
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Atienza, Felipe; Climent, Andreu M; Guillem, María S et al. (2015) Frontiers in noninvasive cardiac mapping rotors in atrial fibrillation-body surface frequency-phase mapping. Card Electrophysiol Clin 7:59-69
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