The molecular basis of cardiac differentiation control

心脏分化控制的分子基础

基本信息

批准号：
10460174
负责人：
Ivan Paul Moskowitz
金额：
$ 57.45万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

项目摘要

Congenital Heart Disease (CHD) is the most common class of life-threatening birth defect. Whereas hundreds of genes have been implicated in CHD, the mechanistic basis of abnormal cardiac morphogenesis causing CHD is unknown in almost all cases. Our work on Hedgehog signaling and CHD over the last decade has culminated in the novel hypothesis that loss of Hedgehog signaling causes a failure of stereotypical control of cardiac progenitor differentiation timing as an underlying cause of CHD. This work may highlight molecular control of differentiation timing as a cornerstone of cardiac development with defects in differentiation timing as a candidate mechanism underlying CHD etiology. This proposal is formed from a decade of study of the molecular mechanisms underlying Atrioventricular septal defects (AVSDs). AVSDs are a serious form of CHD in humans, comprising 5-10% of all CHD and a greater proportion of cases with significant morbidity and mortality1. We have previously contributed to a paradigm shift in the understanding of AV septation, demonstrating that cilia-based Hedgehog (Hh) signaling is required in second heart field (SHF) cardiac progenitors, rather than in the heart itself, for AV septation. Our laboratory has implicated cilia, Hedgehog signaling, and cardiogenic transcription factors in the SHF for AV septation. In preliminary results, our recent work demonstrates that Hh signaling controls SHF progenitor differentiation delay and that removal of Hh signaling causes precocious cardiac differentiation. In this proposal we harness this novel paradigm for cardiac differentiation control to address the genetic and molecular mechanisms underlying cardiac morphogenesis. In Specific Aim 1, we directly interrogate the relationship between cardiac differentiation and cardiac morphogenesis to determine the relationship between Hh signaling, cardiac progenitor differentiation control, and cardiac morphogenesis. In Specific Aim 2, we will investigate the Forkhead box transcription factor gene Foxf1 as a Hh-target gene and candidate mediator of SHF differentiation delay; and in Specific Aim 3, we will identify the diversity of developmental lineages in the SHF and in which lineages Hh signaling acts as a differentiation control switch. If successful, these aims will contribute to a mechanistic understanding of AVSDs and support a novel paradigm for Hh signaling control of differentiation timing. !

先天性心脏病（CHD）是最常见的一类危及生命的出生缺陷。尽管数百个基因与先心病有关，但异常的机制基础几乎所有病例中导致冠心病的心脏形态发生都是未知的。我们在《刺猬》上的工作过去十年中，信号传导和冠心病的研究达到了顶峰，提出了一个新的假设： Hedgehog信号传导导致心脏祖细胞分化的典型控制失败时机作为 CHD 的根本原因。这项工作可能强调分化的分子控制计时作为心脏发育的基石，但分化计时存在缺陷 CHD 病因学的候选机制。该提案是经过十年的分子机制研究而形成的房室间隔缺损（AVSD）。 AVSD 是人类先心病的一种严重形式，包括占所有 CHD 的 5-10%，并且较大比例的病例具有显着的发病率和死亡率1。我们之前对 AV 间隔理解的范式转变做出了贡献，证明第二心脏区域 (SHF) 需要基于纤毛的 Hedgehog (Hh) 信号传导心脏祖细胞，而不是心脏本身，用于房室间隔。我们的实验室已经受到牵连纤毛、Hedgehog 信号传导和 SHF 中用于 AV 分隔的心原性转录因子。在初步结果，我们最近的工作表明 Hh 信号控制 SHF 祖细胞分化延迟和 Hh 信号传导的去除会导致心脏分化早熟。在本提案中，我们利用这种新颖的心脏分化控制范例来解决心脏形态发生的遗传和分子机制。在具体目标 1 中，我们直接询问心脏分化和心脏形态发生之间的关系确定 Hh 信号传导、心脏祖细胞分化控制和心脏形态发生。在特定目标 2 中，我们将研究叉头盒转录因子基因 Foxf1 作为 Hh 靶基因和 SHF 分化延迟的候选介质；和在具体目标 3 中，我们将确定 SHF 中发育谱系的多样性，其中谱系 Hh 信号传导充当分化控制开关。如果成功的话，这些目标将有助于对 AVSD 的机械理解并支持 Hh 的新颖范式分化时间的信号控制。！