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，因为异常心脏生长是心肌病的一个子集的基础，而出生后心肌细胞增殖不足对再生性心脏病治疗构成障碍。新出现的数据表明，转录辅助调节因子YAP 1是细胞增殖和器官大小的重要调节因子。我们实验室和其他实验室的最新研究表明，YAP 1通过促进心肌细胞增殖，包括通常退出细胞周期的小梁和新生心肌细胞的增殖，来关键性地调节心脏生长。其他初步数据表明，YAP 1对正常成人心脏功能至关重要。有趣的是，我们还发现YAP 1与斑珠蛋白结合，斑珠蛋白是一种人类心肌病基因，形成细胞粘附连接，并且可能在细胞核中具有额外的活性。在本提案中，我们将扩大 这些结果，以深入了解YAP 1对心脏生长，功能和再生的调节。在第一个目标，我们将测试的假设，抑制Hippo激酶信号上游的YAP 1是必要的，以限制过度的小梁心肌细胞增殖。在第二个目标中，我们测试的假设，即YAP 1介导的含斑珠蛋白的细胞粘附连接的核信号，以调节胎儿心脏的生长和成人心脏功能。在第三个目标中，我们检验了YAP 1功能获得增强心肌损伤模型中心肌再生的假设。这些目标的成功实现将为改善心脏功能和刺激心肌再生的努力提供信息。

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.