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是有效的心脏再生治疗所必需的。大多数哺乳动物心肌细胞经历终末分化，并在出生后不久从增殖迅速转变为肥大，导致双核。然而，一小部分分化中的未成熟和单核心肌细胞，类似于出生前的心肌细胞，可能保持增殖能力，并进入细胞周期以产生新的心肌细胞。本项目旨在研究经典的Wnt/b-catenin信号和Brahma相关基因1(BRG1)染色质重塑复合体在出生后心脏发育和急性心肌梗死期间心脏细胞周期的进展和退出中的作用。我们的初步数据表明，结肠癌中经常突变的肿瘤抑制因子--结肠腺瘤性息肉病(APC)是一个潜在的关闭心肌细胞增殖的主开关，但APC如何调节心脏细胞周期仍然是一个悬而未决的问题。需要检验的中心假设是，Wnt/b-catenin活性的下降是否会导致出生后BRG1基因的下调，并直接导致心脏从增殖到肥大的转变。我们进一步认为BRG1对于心脏细胞周期进程是足够的和必需的。利用基因治疗、心脏特异的基因靶向和突变，我们将建立Wnt信号和BRG1染色质重塑复合体功能获得和丧失的模型。通过这些模型，我们将追求以下特定的目标：1)确定APC和b-catenin在CMS生后增生-肥大转变中的作用；2)探讨BRG1在出生后心脏发育和急性心肌梗死后b-catenin信号转导中的作用。我们的最终目标是确定操纵b-连环蛋白信号和BRG1染色质重塑复合体是否能够刺激急、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.