YAP1 Regulation of cardiomyocyte proliferation, function, and regeneration

描述(申请人提供)：为了更好地治疗心脏病，需要更好地了解心脏生长控制机制，因为心脏异常生长是心肌病的一个子集，而出生后心肌细胞增殖不足会对再生性心脏病的治疗构成障碍。新的数据表明，转录辅助调节因子YAP1是细胞增殖和器官大小的根本重要调节因子。我们实验室和其他实验室最近的研究表明，YAP1通过促进心肌细胞增殖，包括正常情况下退出细胞周期的小梁细胞和新生心肌细胞的增殖，对心脏生长起关键调节作用。更多的初步数据表明，YAP1对于正常的成人心脏功能是必不可少的。有趣的是，我们还发现YAP1与白蛋白结合，这是一种人类心肌病疾病基因，形成细胞黏附连接，可能在细胞核中具有额外的活动。在这项提议中，我们将扩展 以深入了解YAP1对心脏生长、功能和再生的调控。在第一个目标中，我们将检验这样一个假设，即抑制YAP1上游的河马蛋白激酶信号是限制小梁细胞过度增殖所必需的。在第二个目的中，我们验证了YAP1通过含有蛋白的细胞黏附连接来调节胎儿心脏发育和成人心脏功能来介导核信号的假设。在第三个目的中，我们在心肌损伤模型中验证了YAP1功能增强促进心肌再生的假设。这些目标的成功实现将有助于改善心脏功能和刺激心肌再生的努力。

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.