Signaling and Transcriptional Networks in Cardiac Patterning

描述(由申请人提供)： 先天性心脏畸形是人类最常见的出生缺陷，发生在近1%的 世界各地的人口。通常，它们是由早期祖先的异常血统决定或 图案化的中断，都会导致形态发生缺陷。此外，心脏病是美国成年人的头号杀手。破译心脏形成的秘密可能会导致利用干细胞生物学的潜力修复或再生受损心肌的新方法。该PPG的总体目标是集中多个研究人员的努力，剖析决定心脏独特区域心脏分化早期决定的信号和转录途径，并揭示指导心脏发生过程中模式事件的机制。以一种协调的方式，我们将检验这一假设，即特定的信号和转录网络管理心肌不同区域的决定，并导致特定的亚类决定和心脏功能区域的模式。该项目和核心领导人已经合作了几年，该提议源于共同和互补的利益和方法。项目1将确定规范的Wnt/？-catenin信号及其下游转录事件在体内促进小鼠心脏特定区域的心脏增殖和分化的机制。这一知识将得到补充，并用于操纵胚胎干细胞进入心肌细胞的命运。项目2将探索隔区和房室交界处心肌细胞分化的潜在机制，特别是当它们与小鼠心脏构型过程中关键转录因子如Tbx5和NKX2.5的功能有关时；这将在体内和ES细胞中完成，如项目1。项目3将确定Bmp4使流出道心肌模式影响小鼠室-动脉交界处瓣膜形成的机制，并将使用依赖于MEF2的瓣膜增强剂来剖析导致区域特异性基因表达的信号网络。该项目与项目2的瓣膜兴趣重叠，还将整合参与瓣膜形成和可能的MEF2C激活的Wnt信号。三个科学核心将支持拟议的实验，以及一个行政核心。这项建议中的协同和相辅相成的项目和核心结合了小鼠遗传学、干细胞生物学、细胞生物学、发育生物学和基因组学的专业知识，以解决发育中心脏的模式这一根本问题，特别是与疾病有关的问题。

DESCRIPTION (provided by applicant): Congenital heart malformations, the most common human birth defects, occur in nearly 1% of the population worldwide. Typically, they result from abnormal lineage decisions of early progenitors or disruptions in patterning, both leading to morphogenetic defects. In addition, heart disease is the leading killer of adults in the U.S. Deciphering the secrets of heart formation might lead to novel approaches to repair or regenerate damaged heart muscle by harnessing the potential of stem cell biology. The overall goal of this PPG is to focus the efforts of multiple investigators to dissect the signaling and transcriptional pathways that dictate early decisions of cardiac differentiation in unique regions of the heart and to reveal the mechanisms that guide patterning events during cardiogenesis. In a coordinated fashion, we will test the hypothesis that specific signaling and transcriptional networks govern the decisions of distinct regions of myocardium and result in specific sublineage decisions and patterning of functional regions of the heart. The project and core leaders have been collaborating for several years, and the proposal arises from mutual and complementary interests and approaches. Project 1 will determine the mechanisms by which canonical Wnt/?-catenin signaling and its downstream transcriptional events promote cardiac proliferation and differentiation in specific domains of the mouse heart in vivo. This knowledge will be complemented by and used to manipulate embryonic stem (ES) cells into the cardiomyocyte fate. Project 2 will explore the mechanisms underlying the differentiation of cardiomyocytes in the septal region and at the atrioventricular boundary, particularly as they relate to the function of key transcription factors such as Tbx5 and Nkx2.5 during patterning of the mouse heart; this will be done in vivo and in ES cells, as in Project 1. Project 3 will determine the mechanism by which Bmp4 patterns the outflow tract myocardium to influence valve formation at the ventriculo-arterial boundary in mice and will use a Mef2-dependent valvular enhancer to dissect the signaling networks leading to domain-specific gene expression. This project overlaps with the valve interests of Projects 2 and will also integrate the Wnt signals involved in valvulogenesis and possibly Mef2c activation. Three scientific cores will support the proposed experiments, as well as an administrative core. The synergistic and mutually reinforcing projects and cores in this proposal combine expertise in mouse genetics, stem cell biology, cell biology, developmental biology and genomics to tackle the fundamental problem of patterning of the developing heart, particularly as it relates to disease.