Signaling and Transcriptional Networks in Cardiac Patterning

描述（由申请人提供）： 先天性心脏畸形是最常见的人类出生缺陷，发生在近1%的婴儿中。 全球人口。通常，它们是由早期祖细胞的异常谱系决定或 图案的破坏，两者都导致形态发生缺陷。此外，心脏病是美国成年人的头号杀手，破解心脏形成的秘密可能会导致通过利用干细胞生物学的潜力来修复或再生受损心肌的新方法。本PPG的总体目标是集中多个研究者的努力，剖析决定心脏独特区域心脏分化早期决定的信号传导和转录途径，并揭示心脏发生期间指导模式化事件的机制。在一个协调的方式，我们将测试的假设，即特定的信号和转录网络管理心肌的不同区域的决定，并导致特定的亚系的决定和心脏的功能区域的图案。该项目和核心领导人已经合作了几年，该提案源于相互和互补的利益和方法。项目1将确定规范Wnt/？-连环蛋白信号传导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。这一知识将得到补充，并用于操纵胚胎干细胞（ES）进入心肌细胞的命运。项目2将探索隔区和房室边界心肌细胞分化的机制，特别是当它们与小鼠心脏模式形成过程中关键转录因子如Tbx 5和Nkx2.5的功能相关时;这将在体内和ES细胞中完成，如项目1所述。项目3将确定Bmp 4模式化流出道心肌以影响小鼠心室动脉边界处瓣膜形成的机制，并将使用Mef 2依赖性瓣膜增强子来剖析导致结构域特异性基因表达的信号网络。该项目与项目2的瓣膜利益重叠，并且还将整合涉及瓣膜发生和可能的Mef 2c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。该提案中的协同增效和相互加强的项目和核心联合收割机结合了小鼠遗传学、干细胞生物学、细胞生物学、发育生物学和基因组学方面的专业知识，以解决发育中心脏模式的基本问题，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.