Impaired contraction and/or relaxation of cardiac muscle causes heart failure, a leading cause of cardiovascular morbidity and mortality. Troponin I (TnI) is a key regulator of muscle contractility and heart function. Our research project is to study a recently discovered posttranslational modification of cardiac TnI (cTnI) for its role in enhancing cardiac function and the potential in translational development of new treatment for diastolic heart failure, a challenging clinical condition that represents nearly half of all heart failure cases and currently lacks effective treatment. Comparing to the TnI isoforms in skeletal muscle, cTnI has a unique N-terminal extension that is an adult heart-specific structure containing ?-adrenergic regulated protein kinase A (PKA) phosphorylation sites. Recent studies demonstrated that the N-terminal extension of cTnI can be removed by restrictive proteolysis. This posttranslational modification of cTnI occurs at low levels in normal hearts, and is up- regulated during cardiac adaptations to hemodynamic stresses and heart failure. The resultant N-terminal truncated cTnI (cTnI-ND) remains in cardiac myofilaments and imposes functional effects on the contractility of cardiac muscle. Transgenic over-expression of cTnI-ND in mouse hearts increases relaxation velocity, improves ventricular filling, and increases stroke volume. The enhancement of cardiac function by cTnI-ND suggests that this novel posttranslational modification is non-destructive and may serve as an adaptive mechanism to compensate for diastolic dysfunction in heart failure. To test this hypothesis, we shall characterize the functionof cTnI-ND in enhancing the diastolic function of cardiac muscle and its potential application in the treatment of diastolic heart failure.
Four Specific Aims will be pursued:
Aim 1 is to determine the effects and mechanisms of cTnI-ND on modifying troponin function and cardiac muscle contractility.
Aim 2 is to characterize the function of cTnI-ND in Frank-Starling response of the heart.
Aim 3 is to investigate the production of cTnI-ND in cardiac muscle.
Aim 4 is to understand the long-term effects of cTnI-ND on cardiac function and adaptation. Our previous studies have laid a solid foundation for this new research project. We have substantial amounts of published and preliminary data to support the hypothesis and validate the experimental approaches. The PI and collaborators have formed a synergistic team with complementary expertise to carry out this multi-level investigation. We have previously demonstrated effective collaborations with joint publications. By comprehensively understanding the function and production of cTnI-ND, this study will gain the necessary knowledge for translating a novel molecular mechanism into a new therapeutic approach for the treatment of diastolic heart failure.
Heart failure is the most common cause of morbidity and mortality of heart diseases. Approximately five million people in the United States currently suffer from heart failure with nearly 300,000 annual deaths. More than half-million new cases are diagnosed each year. Despite continuing improvement in the treatment of heart diseases, heart failure remains a major medical challenge and an economic burden on healthcare. More effective treatments are urgently needed. Contraction of the cardiac muscle is the basis of heart function. Cardiac troponin I is a key regulatory protein in cardiac muscle. We recently discovered that the N-terminal extension of cardiac troponin I can be removed by restrictive proteolysis in normal heart and up-regulated in cardiac adaptation to hemodynamic stresses and heart failure. The N-terminal truncated cardiac troponin I facilitates the filling of heart chambers to increase cardiac output, suggesting an attractive new target for the treatment of heart failure, especially diastolic heart failure that is a current clinical challenge with no effetive treatment. Our research project combines the complementary expertise of several research laboratories to study the function and production of N-terminal truncated cardiac troponin I for the ultimate goal of translating this novel molecular mechanism into the development of a new treatment for diastolic heart failure.
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| Liu, Rong; Hossain, M Moazzem; Chen, Xuequn et al. (2017) Mechanoregulation of SM22?/Transgelin. Biochemistry 56:5526-5538 |
| Mondal, Anupom; Jin, J-P (2016) Protein Structure-Function Relationship at Work: Learning from Myopathy Mutations of the Slow Skeletal Muscle Isoform of Troponin T. Front Physiol 7:449 |
| Liu, Rong; Jin, J-P (2016) Deletion of calponin 2 in macrophages alters cytoskeleton-based functions and attenuates the development of atherosclerosis. J Mol Cell Cardiol 99:87-99 |
