Nuclear beta-catenin signaling in the heart

心脏中的核β-连环蛋白信号传导

基本信息

批准号：
8692588
负责人：
Faqian Li
金额：
$ 37.85万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-18 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8692588
关键词：
ATP phosphohydrolase Acute Acute myocardial infarction Adenomatous Polyposis Coli Adult Affect Binding Sites Birth Cardiac Cardiac Myocytes Catalytic Domain Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Fraction Cell Nucleus Cell Proliferation Cells Chromatin Remodeling Factor Chronic Colon Carcinoma Congenital Heart Defects Consensus Cyclin D1 Data Development Down-Regulation Engraftment Genes Genetic Genetic Transcription Glycogen Synthase Kinase 3 Goals Growth Heart Heart Diseases Human Hyperplasia Hypertrophy In Situ Infarction Injury Intervention Link Location Lysine Methods Modeling Molecular Mus Mutagenesis Mutate Myocardial Neonatal Nuclear Nuclear Localization Signal Nuclear Translocation Organ Phenotype Phosphorylation Phosphotransferases Point Mutation Population Proliferating Proliferation Marker Recruitment Activity Regenerative Medicine Role Signal Transduction Site Testing Transcriptional Activation Tumor Suppressor Proteins base beta catenin brahma c-myc Genes cardiac regeneration cardiac repair cardiogenesis cdc Genes chromatin immunoprecipitation chromatin remodeling cyclin D2 gene therapy loss of function new therapeutic target novel novel therapeutic intervention postnatal prenatal prevent promoter stomach cardia

项目摘要

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.

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，必不可少。大多数哺乳动物的心肌细胞经历了末端分化，并迅速从增生转向肥大，导致出生后的双核。但是，与产前相似的少数分化但未成熟和单核心肌细胞的人群可能会保持增生能力，并可能进入细胞周期以产生新的心肌细胞。该项目旨在确定规范Wnt/ B-catenin信号传导和梵天相关的基因1（BRG1）染色质重塑复合物在心脏细胞周期进展中的染色质重塑复合物，并在产后心脏发育和急性心肌梗塞期间出现。我们的初步数据表明，在结肠癌中经常突变的腺瘤性息肉病（APC）是一种潜在的主开关，它会关闭心肌细胞增殖，但是APC如何调节心脏细胞周期仍然是未解决的问题。测试的中心假设是Wnt/B-catenin活性的下降是否导致出生后BRG1下调，并且直接导致了从Cardia增殖到肥大的过渡。我们进一步提出，BRG1足以进行心脏细胞周期进程。使用基因疗法，心脏特异性遗传靶向和诱变，我们将创建模型，以获得Wnt信号传导和BRG1染色质重塑复合物的功能丧失和功能丧失。使用这些模型，我们将追求这些特定目的：1）确定CMS产后增生性杂化过渡期间APC和B-catenin在CMS中的作用； 2）研究BRG1在产后心脏发育和急性心肌梗塞后B- catenin信号传导中的作用。我们的最终目标是确定操纵B-catenin信号传导和BRG1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。