Morphogenesis and growth of the ventricular wall in development and disease

发育和疾病中心室壁的形态发生和生长

• 批准号: 10495945
• 负责人: Anthony B. Firulli
• 金额: $ 279.75万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10495945
• 关键词: Address; Adult; Animal Model; Applications Grants; Area; BHLH Protein; Cardiac; Cardiac Myocytes; Cardiac conduction system; Cell Differentiation process; Child; Chromatin; Complex; Congenital Abnormality; Congenital Heart Defects; Cues; DNA; DNA Binding; Data; Defect; Development; Disease; Embryo; Enhancers; Epigenetic Process; Etiology; Event; Family member; Fingers; Genes; Genetic; Genetic Transcription; Genome; Growth; Health; Heart; Human; Image; Intervention; Knock-out; Laboratories; Left; Left ventricular structure; Life; Link; Lysine; Mediating; Mesoderm; Methylation; Methyltransferase; Mission; Modeling; Molecular; Morphogenesis; Morphology; Mus; Mutate; N-Cadherin; National Heart, Lung, and Blood Institute; Pathogenesis; Pathway interactions; Patients; Pattern; Phenocopy; Physiology; Population; Pregnancy; Prevalence; Prevention; Primitive Streaks; Program Research Project Grants; Proliferating; Proteins; Public Health; Publishing; ROCK1 gene; Regulation; Research; Research Personnel; Research Proposals; Role; Sarcomeres; Side; Signal Pathway; Signal Transduction; Situs Inversus; Specific qualifier value; Testing; United States; United States National Institutes of Health; Variant; Ventricular; Ventricular septum; Work; Zebrafish; cardiogenesis; eHAND helix-loop-helix protein; embryonic stem cell; epigenetic regulation; gastrulation; gene regulatory network; histone methyltransferase; histone modification; human disease; induced pluripotent stem cell; insight; migration; mutant; novel; papillary muscle; planar cell polarity; progenitor; programs; stem cell growth; stem cells; transcription factor; transcriptomics

ABSTRACT Congenital heart defects (CHDs) are the most commonly encountered birth defect. Despite its prevalence, the underlying molecular etiology of most CHDs is not yet known. The central theme of this Program Project Grant application is to elucidate mechanisms that regulate growth and morphogenesis of the ventricle during development. Our objectives are to better understand how epigenetic, transcriptional, and cell signaling regulation within cardiac progenitor cells (CPCs) and embryonic cardiomyocytes impact cardiac specification, differentiation, and ventricular morphogenesis. Four highly interactive and complementary Projects are proposed. Project 1 will study the molecular mechanisms contributing to the genesis of CHDs in early CPCs. These studies build on work from Dr. Stephanie Ware’s laboratory and will test the overall hypothesis that severe CHDs encountered in patients with ZIC3 X-linked heterotaxy result from abnormalities in cardiac progenitor cell fate. Such mechanisms would explain why the spectrum of CHDs encountered in these patients is more severe than what would be anticipated as a result of altered sidedness. Project 2 will study the epigenetic mechanisms regulating the bHLH transcription factor HAND1, which is critical for left ventricular, papillary muscle, and cardiac conduction system (CCS) morphogenesis. These studies build on work from Dr. Anthony Firulli’s laboratory and will test the overall hypothesis that epigenetic regulation of HAND1 transcription directs normal cardiomyocyte patterning. Other studies will identify HAND1 DNA occupancy and interacting transcriptional partners, and thus establish the gene regulatory networks regulating left ventricle, papillary muscle, and CCS morphogenesis. Project 3 will study epigenetic mechanisms critical to mesendoderm specification and cardiogenic differentiation. These studies build on work from Dr. Weinian Shou’s laboratory and will test the overall hypothesis that the lysine methyltransferase SMYD4 regulates Histone modifications essential for establishing correct numbers of CPCs. Project 4 will study the role of a novel planar cell polarity effector protein, SHROOM3, in the pathogenesis of CHDs. These studies build on work from Dr. Matthew Durbin’s laboratory and will test the overall hypothesis that SHROOM3 interacts at a number of key points within the PCP pathway, and that identified rare CHD patient- specific SHROOM3 variants disrupt PCP within cardiomyocytes. The proposed work will be facilitated by the participation of three cores (Core A – Administration; Core B - Embryonic stem cell growth and genetically modified models; and Core C - Cardiac physiology and imaging). Ultimately, the studies proposed in this Program Project Grant application will illustrate how epigenetic, transcriptional, and signaling mechanisms occurring within both cardiac progenitors and embryonic cardiomyocytes establish the gene regulatory networks necessary for cardiac morphogenesis. Importantly, defining the molecular mechanisms of these events will inform interventions aiming to mitigate deleterious impacts of CHD.

抽象的 先天性心脏病（CHD）是最常见的出生缺陷。尽管其盛行， 大多数先心病的潜在分子病因尚不清楚。本计划项目资助的中心主题 应用旨在阐明调节心室生长和形态发生的机制 发展。我们的目标是更好地了解表观遗传、转录和细胞信号传导如何 心脏祖细胞（CPC）和胚胎心肌细胞内的调节影响心脏规格， 分化和心室形态发生。四个高度互动和互补的项目是 建议的。项目1将研究早期CPC中CHD发生的分子机制。 这些研究建立在 Stephanie Ware 博士实验室的工作基础上，并将检验以下总体假设：严重的 ZIC3 X连锁异位性患者的先天性心脏病是由心脏祖细胞异常引起的 命运。这种机制可以解释为什么这些患者所患的冠心病更为严重 比由于改变侧面而预期的结果。项目2将研究表观遗传机制 调节 bHLH 转录因子 HAND1，这对于左心室、乳头肌和心脏至关重要 传导系统（CCS）形态发生。这些研究建立在 Anthony Firulli 博士实验室的工作基础上 将检验 HAND1 转录的表观遗传调控指导正常心肌细胞的总体假设 图案化。其他研究将确定 HAND1 DNA 占据和相互作用的转录伙伴，从而 建立调节左心室、乳头肌和 CCS 形态发生的基因调控网络。 项目 3 将研究对中内胚层规范和心源性分化至关重要的表观遗传机制。 这些研究建立在寿伟年博士实验室的工作基础上，并将检验总体假设： 赖氨酸甲基转移酶 SMYD4 调节组蛋白修饰，这对于建立正确的赖氨酸数量至关重要 每次点击费用。项目4将研究新型平面细胞极性效应蛋白SHROOM3在发病机制中的作用 的先心病。这些研究建立在 Matthew Durbin 博士实验室的工作基础上，并将检验总体假设 SHROOM3 在 PCP 通路内的许多关键点上相互作用，并鉴定出罕见的 CHD 患者 特定的 SHROOM3 变异会破坏心肌细胞内的 PCP。拟议的工作将由 三个核心的参与（核心 A – 管理；核心 B – 胚胎干细胞生长和遗传 修改模型；和核心 C - 心脏生理学和成像）。最终，本计划中提出的研究 项目拨款申请将说明表观遗传、转录和信号传导机制如何发生在 心脏祖细胞和胚胎心肌细胞都建立了必要的基因调控网络 心脏形态发生。重要的是，定义这些事件的分子机制将为干预措施提供信息 旨在减轻冠心病的有害影响。