Grant Details
Description
DESCRIPTION (provided by applicant): The long range goal of the proposed experiments is to understand the function of myosin binding protein-C in the regulation of cardiac contraction. Mutations in cardiac myosin binding protein-C (cMyBPC) account for nearly half of all instances of inherited hypertrophic cardiomyopathy and cMyBP-C is phosphorylated in response to inotropic stimuli, but neither the mechanisms by which mutations in cMyBP-C cause disease nor the role of cMyBP-C in mediating cardiac contractile responses are well understood. Until now the central difficulty in addressing the function of MyBP-C has been the inability to systematically alter cMyBP-C content or to selectively affect cMyBP-C phosphorylation state without simultaneously affecting other myofilament proteins. However, both these technical limitations will be overcome in the proposed experiments by using cMyBP-C knockout mice that lack cMyBP-C in heart. The cMyBP-C knockout mice therefore provide a "null" background on which to test specific mechanistic hypotheses of cMyBP-C function in health and disease. Based on our initial studies characterizing the cMyBP-C knockout mice, the working hypothesis guiding these experiments is that cMyBP-C normally acts to limit cross-bridge kinetics and power output and that phosphorylation of cMyBP-C relieves this inhibition. We further propose that the contractile effects of cMyBP-C are mediated by binding to myosin at two distinct sites and effects elicited by cMyBP-C binding differ depending on whether one or both sites are occupied. As a corollary to this idea, we propose that unregulated binding of the cMyBP-C N-terminus to myosin S2, as might occur in some familial hypertrophic cardiomyopathies, is sufficient to cause cardiomyopathy. These hypotheses will be tested in four Specific Aims designed to determine 1) contractile effects of cMyBP-C binding to distinct myosin binding sites, alone and in combination; 2) steps in the cross-bridge cycle affected by cMyBP-C binding to myosin S2; 3) the role of cMyBP-C phosphorylation in mediating contractile responses to padrenergic stimuli; and 4) whether expression of cMyBP-C N-terminal regulatory sequences is sufficient to induce cardiac hypertrophy in a dominant negative fashion. Results from the proposed experiments will provide new and relevant information regarding the function of MyBP-C, mechanisms of myosin regulation, and mechanisms by which mutations in the cMyBP-C cause human disease.
Status | Finished |
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Effective start/end date | 9/1/05 → 1/31/17 |
Funding
- National Institutes of Health: $324,278.00
- National Institutes of Health: $6,261.00
- National Institutes of Health: $339,423.00
- National Institutes of Health: $367,883.00
- National Institutes of Health: $364,350.00
- National Institutes of Health: $347,500.00
- National Institutes of Health: $371,505.00
- National Institutes of Health: $324,278.00
- National Institutes of Health: $324,278.00
- National Institutes of Health: $359,705.00
- National Institutes of Health: $234,944.00
- National Institutes of Health: $371,647.00
ASJC
- Medicine(all)
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