Role of Meis1 in Regulation of Cardiomyocyte Proliferation

描述(申请人提供)：心力衰竭是一种代价高昂且致命的疾病，全世界有2300多万患者受到影响，美国有580万患者，其中一半人在确诊后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。由心肌细胞丢失引起的收缩性心力衰竭是心力衰竭的主要原因。心力衰竭病理生理学的核心是成人心脏不能再生。取而代之的是，丢失的心肌细胞被纤维组织取代，这会导致进行性重塑、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，主要是通过预先存在的心肌细胞的增殖。此外，我们发现Meis1是哺乳动物出生后心肌细胞增殖的关键调节因子。我们在心肌细胞中使用靶向MEIS1缺失的初步结果表明，MEIS1的缺失会导致成人心脏中心肌细胞的强劲增殖。最后，我们确定细胞周期抑制因子p1和p21是心肌细胞MEIS1的潜在靶点。因此，我们假设Meis1通过转录激活p16和p21来调节心肌细胞的增殖。我们将利用MEIS1功能丧失和功能获得的小鼠模型，以及一系列体内和体外技术来解决这一假说。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新的心血管疾病的发病机制和治疗方法。 与公共卫生相关：心力衰竭是一种代价高昂且致命的疾病，在美国有500多万患者受到影响，其中一半人在确诊后5年内死亡。这个项目的目的是 就是决定如何让成人的心脏细胞分裂。这可能会导致心脏疾病的治愈。 通过发现成人心脏再生的新策略而失败。

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. PUBLIC HEALTH RELEVANCE: Heart failure is a costly and deadly disease affecting over 5 million patients in America, half of which die within 5 years of diagnosis. The aim of this project is to determine how to make adult heart cells divide. This can potentially lead to a cure for heart failure by uncovering new strategies for regeneration of the adult heart.