Familial Hypertrophic Cardiomyopathy (FHC) is an autosomal dominant disease, which has been associated with mutations in almost every major cardiac sarcomeric protein. Whereas individuals with myosin heavy chain (MHC) mutations, in general, have a higher level of cardiac hypertrophy, those with cardiac Troponin T (CTnT) and some of the reported Troponin I (CTnI) mutations have less hypertrophy and a higher incidence of sudden cardiac death (SCD). Most recently, a single mutation in Troponin C has been reported to be possibly associated with FHC. Although several mutations have been extensively characterized in vitro, it is still unclear how they cause cardiac hypertrophy or SCD. Our working hypothesis is that FHC troponin mutations alter the pCa-force and -ATPase relationships, the ability of the muscle to develop maximum force and ATPase activity, myosin cross-bridge kinetics, efficiency of contraction, and the ability of the muscle to do work. That mutations, which increase Ca2+- sensitivity, are more closely associated with sudden death, while mutations, which decrease the ability of the muscle to develop force, are more closely associated with hypertrophy. Recently reported transgenic mouse results along with our data from three transgenic mouse lines expressing the human CTnT (HCTnT) FHC mutations (I79N, F1101 and R278C) and HCTnI-R145G, support this hypothesis. The objective of this proposal is to comprehensively study the in vitro consequences (e.g. Ca2+-sensitivity of contraction, kinetics of force development/relaxation, impaired CTnI inhibitory function, etc.) of different FHC associated Troponin mutations in existing and new transgenic mice to identify the key mechanisms involved in the pathogenesis of FHC. This application brings together highly talented scientists at the University of Miami with varied backgrounds and represents a comprehensive approach to the study of these troponin mutations. Our goal is to correlate, the observed effects of mutations in CTnT, CTnI and CTnC on the Ca2+ regulation of cardiac muscle contraction in our animal models, with the pathogenesis of FHC in humans, especially in cases where sudden cardiac deaths have been reported. These studies will determine the functional consequences of different troponin T, troponin I and troponin C mutations under the same experimental conditions, and thus help identify key mechanism(s) involved in the pathogenesis of Troponin-linked FHC and lead to potential therapeutic strategies

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067415-03
Application #
6781903
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Varghese, Jamie
Project Start
2002-07-25
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$376,506
Indirect Cost
Name
University of Miami School of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
052780918
City
Miami
State
FL
Country
United States
Zip Code
33146
Chang, Audrey N; Greenfield, Norma J; Singh, Abhishek et al. (2014) Structural and protein interaction effects of hypertrophic and dilated cardiomyopathic mutations in alpha-tropomyosin. Front Physiol 5:460
Parvatiyar, Michelle S; Pinto, Jose Renato; Dweck, David et al. (2010) Cardiac troponin mutations and restrictive cardiomyopathy. J Biomed Biotechnol 2010:350706
Wen, Yuhui; Xu, Yuanyuan; Wang, Yingcai et al. (2009) Functional effects of a restrictive-cardiomyopathy-linked cardiac troponin I mutation (R145W) in transgenic mice. J Mol Biol 392:1158-67
Pinto, Jose Renato; Parvatiyar, Michelle S; Jones, Michelle A et al. (2009) A functional and structural study of troponin C mutations related to hypertrophic cardiomyopathy. J Biol Chem 284:19090-100
Dweck, David; Hus, Nir; Potter, James D (2008) Challenging current paradigms related to cardiomyopathies. Are changes in the Ca2+ sensitivity of myofilaments containing cardiac troponin C mutations (G159D and L29Q) good predictors of the phenotypic outcomes? J Biol Chem 283:33119-28
Baudenbacher, Franz; Schober, Tilmann; Pinto, Jose Renato et al. (2008) Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. J Clin Invest 118:3893-903
Landstrom, Andrew P; Parvatiyar, Michelle S; Pinto, Jose R et al. (2008) Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. J Mol Cell Cardiol 45:281-8
Wen, Yuhui; Pinto, Jose Renato; Gomes, Aldrin V et al. (2008) Functional consequences of the human cardiac troponin I hypertrophic cardiomyopathy mutation R145G in transgenic mice. J Biol Chem 283:20484-94
Chang, Audrey N; Parvatiyar, Michelle S; Potter, James D (2008) Troponin and cardiomyopathy. Biochem Biophys Res Commun 369:74-81
Westermann, Dirk; Knollmann, Bjorn C; Steendijk, Paul et al. (2006) Diltiazem treatment prevents diastolic heart failure in mice with familial hypertrophic cardiomyopathy. Eur J Heart Fail 8:115-21

Showing the most recent 10 out of 25 publications