Heart failure remains one of the leading causes of morbidity and mortality. Cardiomyopathy, a primary disorder of cardiac muscle, represents an important yet incompletely understood cause of heart failure. As cardiomyopathy and heart failure are common problems in infants and children, there is need for a better understanding of the molecular underpinnings of these forms of heart disease. Many cases of cardiomyopathy are caused by genetic mutations in the proteins involved in cardiac muscle contraction. Recently, several mutations in alpha myosin, one of the motor proteins of cardiac muscle, have been identified in the cardiac muscle of patients with cardiomyopathy. The progression from mutation to cardiomyopathic phenotype is not well defined. The goal of the proposed training award is to develop the research skill set of a pediatric cardiac surgeon, to enable him to investigate the molecular and functional effects of alpha myosin genetic manipulation. This training program consists of didactic training as well as immersion in a research project, the goal of which is to better understand the role of cardiac motor protein mutations as well as the therapeutic potential that may come from altering motor protein expression. Preliminary data reveal that upregulation of alpha myosin expression may improve contractility in heart failure.
The Aims of the research project are to (1) determine the effects of various engineered alpha myosin mutations on contractile phenotype of isolated cardiac myocytes, and (2) to then determine whether upregulation of wild type alpha myosin motor protein expression through gene transfer can improve contractility in heart failure. These experiments will be performed using state of the art molecular tools, both for gene delivery and physiologic assessment. This project and the associated training will lead to new understanding of the role of motor proteins in normal and failing hearts, and position the candidate for a durable investigational career as an academic pediatric cardiac surgeon.
The overall goal of the application is to assess the results of manipulation of a cardiac motor protein both to induce cardiac dysfunction and to treat it as well.
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