The molecular basis of cardiac differentiation control

心脏分化控制的分子基础

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10460174
• 关键词: Address; Cardiac; Cardiac development; Cardiopulmonary; ChIP-seq; Chromatin; Cilia; Congenital Abnormality; Defect; Development; Erinaceidae; Etiology; Excision; FOXF1 gene; Failure; Genes; Genetic; Heart; Heart Abnormalities; Human; In Vitro; Laboratories; Life; Mediator of activation protein; Molecular; Molecular Profiling; Morbidity - disease rate; Morphogenesis; Mutant Strains Mice; SHH gene; Work; atrioventricular septal defect; base; congenital heart disorder; gene regulatory network; in vivo; mutant; novel; overexpression; premature; progenitor; single cell sequencing; smoothened signaling pathway; transcription factor; transcriptome; transcriptome sequencing

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。 尽管有数百个基因与CHD有关，但异常代谢的机制基础仍然存在。 几乎所有病例中引起CHD的心脏形态发生都是未知的。我们在Hedgehog上的工作 过去十年中，信号传导和CHD的研究最终得出了一个新的假设，即信号传导的丧失 Hedgehog信号传导导致心脏祖细胞分化的常规控制失败 时间是冠心病的根本原因。这项工作可能会突出分化的分子控制 作为心脏发育的基石， 冠心病病因学的潜在机制。 这一建议是从十年的分子机制研究形成的， 房室间隔缺损（AVSD）。AVSD是人类CHD的严重形式，包括 所有CHD的5-10%和具有显著发病率和死亡率的病例的更大比例1。我们 以前曾对房室间隔理解的范式转变做出过贡献， 证明了基于纤毛的Hedgehog（Hh）信号传导在第二心脏区域（SHF）中是必需的 心脏祖细胞，而不是心脏本身，用于AV分隔。我们的实验室发现 纤毛、Hedgehog信号传导和心源性转录因子在AV分隔的SHF中的作用。在 初步结果，我们最近的工作表明，Hh信号控制SHF祖细胞 Hh信号传导的去除导致早熟的心脏分化。 在这项建议中，我们利用这种新的模式，心脏分化控制，以解决 心脏形态发生的遗传和分子机制。在具体目标1中， 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 心脏形态发生在具体目标2中，我们将研究叉头框转录 因子基因Foxf 1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， 谱系Hh信号传导充当分化控制开关。如果成功，这些目标将 有助于对AVSD的机械理解，并支持Hh的新范式 区分定时的信令控制。 !