Improved understanding of cardiac growth control mechanisms is needed to better treat heart disease, as abnormal cardiac growth underlies a subset of cardiomyopathies while inadequate postnatal cardiomyocyte proliferation poses a barrier to regenerative heart disease therapy. Emerging data indicate that the transcriptional co-regulator YAP1 is a fundamentally important regulator of cellular proliferation and organ size. Recent studies from our lab and others indicate that YAP1 critically regulates heart growth by promoting cardiomyocyte proliferation, including proliferation of trabecular and neonatal cardiomyocytes that are normally withdrawing from the cell cycle. Additional preliminary data indicate that YAP1 is essential for normal adult heart function. Intriguingly, we have also found that YAP1 binds plakoglobin, a human cardiomyopathy disease gene that forms cell adhesion junctions and that likely has additional activities in the nucleus. In this proposal we will expand on these results to gain insights into YAP1 regulation of cardiac growth, function, and regeneration. In the first aim, we will test the hypothesis that inhibitory Hippo kinase signaling upstream of YAP1 is required to limit excessive trabecular cardiomyocyte proliferation. In the second aim, we test the hypothesis that YAP1 mediates nuclear signaling by plakoglobin-containing cell adhesion junctions to regulate fetal heart growth and adult heart function. In the third aim, we test the hypothesis that YAP1 gain of function augments myocardial regeneration in myocardial injury models. Successful execution of these aims will inform efforts to improve heart function and stimulate myocardial regeneration.
Heart disease is a leading cause of morbidity and mortality in both children and adults. Improved treatment of heart disease requires better understanding of mechanisms that regulate heart muscle growth, as abnormalities of fetal myocardial growth underlie forms of congenital heart muscle disease, while inadequate adult cardiomyocyte proliferation poses a fundamental barrier to treatment of acquired heart disease. In this proposal we seek to better understand the mechanisms by which the gene YAP1 regulates heart muscle growth and function. These studies will provide new insights into mechanisms that govern heart muscle growth and will inform efforts to improve treatment for heart disease.
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