Contraction of the heart occurs through regulated interactions of the myofilament proteins in response to increasing intracellular calcium concentrations. In heart failure both calcium dynamics and the response of the myofilaments to calcium are altered. These alterations impair systolic and diastolic function and are potentially reversible. This proposal seeks to define specific mechanisms for the effects of variants of the key regulatory protein troponin I which contribute to heart failure and hypertrophy. The hypothesis of this proposal is that post translational or genetic variants cardiac troponin I modify its function and play a central role in heart failure and the response to increased heart rate and afterload. The long-range goal of this work is to understand the underlying molecular mechanism by which these variants alter cardiac function in order to design strategies to prevent or treat cardiac dysfunction. The dissection of the molecular pathophysiology of troponin I variants will be approached in a series of highly collaborative integrative studies focused on modeling of myofilament disease-related post translational or genetic variants changes in vivo in murine models and in human cardiomyocytes. To address these goals the following aims are proposed: 1. To determine the degree and impact of altered site-specific phosphorylation of troponin I in human heart failure by quantitative phosphoproteomics in human cardiomyocytes and expression of recombinant phosphorylation site mutants of troponin I in human cardiomyocytes 2. To determine whether phosphorylation of PKA sites of troponin I or phospholamban are the dominant contributor to the in vivo frequency dependent acceleration of relaxation (FDAR) and the relaxation response to afterload by use of interbred mouse models and 3. To address the hypothesis that an exon 5 sequence variant of troponin I, which occurs with a 3 % frequency in African-Americans, influences the response to acute and chronic afterload through the use of an in vivo murine model. This work should provide insight into the in vivo effects of specific myofilament troponin I variants which contribute to pathophysiology of heart failure and hypertrophy. In the long-term this will assist in the development of novel therapies which address the correction of myofilament defects.

Public Health Relevance

Heart failure is a significant medical problem in the United States. This proposal will study troponin I, a protein which regulates contraction of the heart. The specific goals are to study the effect of genetic and protein modifications of this protein on heart function. In the long term this should assist in developing better treatments for heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063038-10
Application #
7802121
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Przywara, Dennis
Project Start
1999-09-13
Project End
2014-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
10
Fiscal Year
2010
Total Cost
$435,552
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Li, Yuejin; Zhu, Guangshuo; Paolocci, Nazareno et al. (2017) Heart Failure-Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo. Circ Heart Fail 10:
Bales, Nathan D; Johnson, Nicole M; Judge, Daniel P et al. (2016) Comprehensive Versus Targeted Genetic Testing in Children with Hypertrophic Cardiomyopathy. Pediatr Cardiol 37:845-51
Xu, Mingguo; Ramirez-Correa, Genaro A; Murphy, Anne M (2015) Proteomics of pediatric heart failure: from traditional biomarkers to new discovery strategies. Cardiol Young 25 Suppl 2:51-7
Wijnker, Paul J M; Li, Yuejin; Zhang, Pingbo et al. (2015) A novel phosphorylation site, Serine 199, in the C-terminus of cardiac troponin I regulates calcium sensitivity and susceptibility to calpain-induced proteolysis. J Mol Cell Cardiol 82:93-103
Ramirez-Correa, Genaro A; Ma, Junfeng; Slawson, Chad et al. (2015) Removal of Abnormal Myofilament O-GlcNAcylation Restores Ca2+ Sensitivity in Diabetic Cardiac Muscle. Diabetes 64:3573-87
Ramirez-Correa, Genaro A; Frazier, Aisha H; Zhu, Guangshuo et al. (2015) Cardiac troponin I Pro82Ser variant induces diastolic dysfunction, blunts ?-adrenergic response, and impairs myofilament cooperativity. J Appl Physiol (1985) 118:212-23
Jacobs, Jeffrey P; Quintessenza, James A; Karl, Tom R et al. (2015) Summary of the 2015 International Paediatric Heart Failure Summit of Johns Hopkins All Children's Heart Institute. Cardiol Young 25 Suppl 2:8-30
Wijnker, Paul J M; Sequeira, Vasco; Foster, D Brian et al. (2014) Length-dependent activation is modulated by cardiac troponin I bisphosphorylation at Ser23 and Ser24 but not by Thr143 phosphorylation. Am J Physiol Heart Circ Physiol 306:H1171-81
Wijnker, Paul J M; Sequeira, Vasco; Witjas-Paalberends, E Rosalie et al. (2014) Phosphorylation of protein kinase C sites Ser42/44 decreases Ca(2+)-sensitivity and blunts enhanced length-dependent activation in response to protein kinase A in human cardiomyocytes. Arch Biochem Biophys 554:11-21
Ramirez-Correa, Genaro A; Martinez-Ferrando, Maria Isabel; Zhang, Pingbo et al. (2014) Targeted proteomics of myofilament phosphorylation and other protein posttranslational modifications. Proteomics Clin Appl 8:543-53

Showing the most recent 10 out of 39 publications