Role of Meis1 in Regulation of Cardiomyocyte Proliferation

描述（由申请人提供）：心力衰竭是一种昂贵且致命的疾病，全世界有超过2300万患者，美国有580万患者，其中一半在诊断后5年内死亡。此外，心力衰竭每年花费美国政府超过390亿美元的医疗费用。由心肌细胞丧失引起的收缩期心力衰竭是心力衰竭的主要原因。心脏衰竭病理生理学的核心是成人心脏不能再生。相反，失去的肌细胞被纤维组织所取代，导致进行性重塑、扩张和进一步的收缩功能障碍。我们最近发现，新生小鼠的心脏能够在损伤后完全再生，主要是通过原有心肌细胞的增殖。此外，我们发现Meis1是哺乳动物心肌细胞出生后增殖的关键调节因子。我们在心肌细胞中靶向删除Meis1的初步结果表明，Meis1的缺失导致成人心脏中心肌细胞的强劲增殖。最后，我们确定了细胞周期抑制剂p1和p21是心肌细胞中Meis1的潜在靶点。因此，我们假设Meis1通过p16和p21的转录激活来调节心肌细胞增殖。我们将利用Meis1功能丧失和功能获得小鼠模型，以及一系列体内和体外技术来解决这一假设。最终，我们希望利用我们对Meis1在心肌细胞增殖中的作用的理解来揭示心血管疾病的新疾病机制和治疗方法。

DESCRIPTION (provided by applicant): Heart failure is a costly and deadly disease, affecting over 23 million patients worldwide, 5.8 million patients in America, half of which die within 5 years of diagnosis. In addition, heart failure costs the US government over 39 billion Dollars in health care costs annually. Systolic heart failure, resulting from cardiomyocyte loss, is the leading cause of heart failure. At the core of the pathophysiology of heart failure is the inabilit of the adult heart to regenerate. Instead, lost myocytes are replaced by fibrous tissue, which results in progressive remodeling, dilatation, and further contractile dysfunction. We recently discovered that the newborn mouse heart is able completely regenerate following injury, primarily through proliferation of pre-existing cardiomyocytes. Moreover, we identified Meis1 as a key regulator of mammalian cardiomyocyte proliferation post-natally. Our preliminary results using targeted Meis1 deletion in cardiomyocytes indicate that loss of Meis1 results in robust cardiomyocyte proliferation in the adult heart. Finally, we identified the cell cycle inhibitors p1 and p21 as potential targets for Meis1 in cardiomyocytes. Therefore, we hypothesize that Meis1 regulates cardiomyocyte proliferation through transcriptional activation of p16 and p21. We will utilize Meis1 loss of function and gain of function mouse models, as well as an array of in vivo and in vitro techniques to address this hypothesis. Ultimately, we hope to exploit our understanding of the role of Meis1 in cardiomyocyte proliferation to uncover new disease mechanisms and therapeutic approaches for cardiovascular diseases.