YAP1 Regulation of cardiomyocyte proliferation, function, and regeneration

描述（由申请人提供）：需要提高对心脏生长控制机制的理解，以更好地治疗心脏病，因为心脏生长异常是心肌病的一部分，而出生后心肌细胞增殖不足是再生心脏病治疗的障碍。新出现的数据表明，转录共调节剂YAP1是细胞增殖和器官大小的重要调节剂。我们实验室和其他人最近的研究表明，YAP1通过促进心肌细胞增殖，包括正常退出细胞周期的小梁和新生儿心肌细胞的增殖，对心脏生长起到关键调节作用。其他初步数据表明，YAP1对正常成人心脏功能至关重要。有趣的是，我们还发现YAP1与血小板红蛋白结合，血小板红蛋白是一种人类心肌病基因，形成细胞粘附连接，可能在细胞核中有额外的活性。在这个建议中，我们将进行扩展

DESCRIPTION (provided by applicant): 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.