Nuclear beta-catenin signaling in the heart

描述（由申请人提供）：了解控制心脏细胞周期进展和退出的分子机制对于有效的心脏再生治疗至关重要。大多数哺乳动物心肌细胞经历终末分化，并在出生后不久迅速从增生转变为肥大，导致双核化。然而，一小群分化但不成熟的单核心肌细胞，与产前心肌细胞相似，可能保留增殖能力，并可能进入细胞周期产生新的心肌细胞。该项目旨在确定经典Wnt/β-连环蛋白信号传导和brahma相关基因1（Brg 1）染色质重塑复合物在出生后心脏发育和急性心肌梗死期间心脏细胞周期进展和退出中的作用。我们的初步数据表明，结肠腺瘤性息肉病（APC），一种在结肠癌中经常突变的肿瘤抑制因子，是关闭心肌细胞增殖的潜在主开关，但APC如何调节心脏细胞周期仍然是一个悬而未决的问题。要检验的中心假设是，Wnt/b-连环蛋白活性的下降是否导致出生后Brg 1下调，并直接负责从贲门增生到肥大的转变。我们进一步提出，Brg 1是足够的，需要心脏细胞周期的进展。使用基因治疗，心脏特异性遗传靶向和诱变，我们将创建Wnt信号和Brg 1染色质重塑复合物的功能获得和丧失模型。利用这些模型，我们将追求这些特定的目标：1）确定APC和b-连环蛋白在CM出生后增生-肥大转变过程中的作用; 2）研究Brg 1在出生后心脏发育和急性心肌梗死后B-连环蛋白信号传导中的作用。我们的最终目标是确定操纵b-连环蛋白信号和Brg 1染色质重塑复合物是否可以刺激急性和慢性心肌损伤后的心脏再生和修复。

DESCRIPTION (provided by applicant): Understanding the molecular mechanisms that control cardiac cell cycle progression and exit is essential and required for effective cardiac regeneration therapy. The majority of mammalian cardiomyocytes undergoes terminal differentiation and rapidly switches from hyperplasia to hypertrophy resulting in binucleation soon after birth. However, a small population of differentiating but immature and mononucleated cardiomyocytes, similar to prenatal ones, may retain a proliferative ability and could enter the cell cycle to produce new cardiomyocytes. This project aims to determine the roles of canonical Wnt/ b-catenin signaling and the brahma-related gene 1 (Brg1) chromatin remodeling complex in cardiac cell cycle progression and exit during postnatal heart development and acute myocardial infarction. Our preliminary data suggest that adenomatous polyposis coli (APC), a tumor suppressor frequently mutated in colon cancer, is a potential master switch that turns off cardiomyocyte proliferation, but how APC regulates the cardiac cell cycle remains an unanswered question. The central hypothesis to test is if the decline of Wnt/b-catenin activity leads to Brg1 downregulation after birth and is directly responsible for the transition from cardia proliferation to hypertrophy. We further propose that Brg1 is sufficient and required for cardiac cell cycle progression. Using gene therapy, cardiac-specific genetic targeting and mutagenesis, we will create models for gain- and loss-of-function in Wnt signaling and the Brg1 chromatin remodeling complex. With these models, we will pursue these specific aims: 1) To determine the roles of APC and b-catenin in CMs during the postnatal hyperplasia-hypertrophy transition of CMs; 2) To investigate the role of Brg1 in b- catenin signaling during postnatal heart development and after acute myocardial infarction. Our ultimate goal is to determine if manipulating b-catenin signaling and the Brg1 chromatin remodeling complex can stimulate cardiac regeneration and repair after acute and chronic myocardial damage.