The cardiac thin filament is the essential regulator of cardiac contractility and relaxation at the molecular level. It is comprised of five discrete proteins: cTnC, cTnI, cTnT, actin and tropomyosin that have co-evolved to sustain efficient cardiac performance at rest, during exercise and, importantly, to respond to pathologic stressors. Mutations in genes encoding each of these proteins have been definitively linked to the development of a range of human genetic cardiomyopathies, including hypertrophic (HCM) and dilated (DCM) forms. Despite 25 years of study to define the direct link(s) between the biophysical insult and the resultant complex cardiomyopathy, many questions remain and significantly limit our ability to use genotype to prognosticate and inform patient management. Recent clinical studies based on genotyped cohorts have established that the earliest stages of pathogenic remodeling precedes the development of overt cardiac hypertrophy or dilatation. This seminal observation raises the possibility that early therapeutic intervention focusing on the earliest molecular ?triggers? may prove successful in slowing the natural history of these complex disorders. To test this hypothesis, the current application builds on our prior funding period where we developed an innovative integrated approach to probing thin filament-linked HCM and DCM that incorporates computation, biophysics and whole-heart physiology. We have identified two distinct, common pathogenic pathways to study.
In Aim 1 we will delineate the dynamic role of the Tropomyosin overlap domain and the coupled allosteric regulation by the cardiac Troponin T N terminus on the differential cardiac remodeling that defines hypertrophic and dilated cardiomyopathies linked to known mutations in the flexible tropomyosin overlap. And in Aim 2 we will define the potential modulatory role of altered cTnC Ca2+ dissociation kinetics in the activation of CaMKII signaling as a nodal point in the pathogenesis of sarcomeric hypertrophic cardiomyopathy. The successful completion of these Aims will both reveal novel disease mechanisms and directly test the potential for altering the natural history of genetic HCM and DCM.

Public Health Relevance

Genetic cardiomyopathies caused by sarcomeric gene mutations represent common and complex clinical disorders that often effect young people. This complexity limits our ability to link genotype to phenotype and significantly limits our ability to treat patients. We have developed a robust integrated computational ? cellular ? whole heart approach that will improve our understanding of how independent mutations cause this complex disorder and lead to better therapeutic options

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Adhikari, Bishow B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Arizona
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Lynn, Melissa L; Lehman, Sarah J; Tardiff, Jil C (2018) Biophysical Derangements in Genetic Cardiomyopathies. Heart Fail Clin 14:147-159
Lynn, M L; Tal Grinspan, L; Holeman, T A et al. (2017) The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy. J Mol Cell Cardiol 108:127-137
Coppini, Raffaele; Mazzoni, Luca; Ferrantini, Cecilia et al. (2017) Ranolazine Prevents Phenotype Development in a Mouse Model of Hypertrophic Cardiomyopathy. Circ Heart Fail 10:
McConnell, Mark; Tal Grinspan, Lauren; Williams, Michael R et al. (2017) Clinically Divergent Mutation Effects on the Structure and Function of the Human Cardiac Tropomyosin Overlap. Biochemistry 56:3403-3413
Tardiff, Jil C (2017) Assessing the Phenotypic Burden of Preclinical Sarcomeric Hypertrophic Cardiomyopathy-New Assessments to Guide Diagnosis and Management. JAMA Cardiol 2:428-429
Behunin, Samantha M; Lopez-Pier, Marissa A; Mayfield, Rachel M et al. (2016) Liver Kinase B1 complex acts as a novel modifier of myofilament function and localizes to the Z-disk in cardiac myocytes. Arch Biochem Biophys 601:32-41
Crocini, C; Ferrantini, C; Scardigli, M et al. (2016) Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy. J Mol Cell Cardiol 91:42-51
Tardiff, Jil C (2016) The Role of Calcium/Calmodulin-Dependent Protein Kinase II Activation in Hypertrophic Cardiomyopathy. Circulation 134:1749-1751
Sequeira, Vasco; Najafi, Aref; McConnell, Mark et al. (2015) Synergistic role of ADP and Ca(2+) in diastolic myocardial stiffness. J Physiol 593:3899-916
Tardiff, Jil C; Carrier, Lucie; Bers, Donald M et al. (2015) Targets for therapy in sarcomeric cardiomyopathies. Cardiovasc Res 105:457-70

Showing the most recent 10 out of 34 publications