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 先天性心脏缺陷（CHD）是最常见的先天缺陷。尽管它的盛行，但 大多数CHD的基本分子病因尚不清楚。该计划项目赠款的中心主题 应用是阐明调节通气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，转录和细胞信号如何 心脏祖细胞内的调节（CPC）和胚胎心肌细胞影响心脏规范， 分化和心室形态发生。四个高度互动和完成的项目是 建议的。项目1将研究促成早期CPC中CHD起源的分子机制。 这些研究以斯蒂芬妮·韦尔（Stephanie Ware）的实验室的工作为基础 ZIC3 X X连锁异际因心脏祖细胞异常引起的CHD遇到的CHD 命运。这种机制可以解释为什么在这些患者中遇到的CHD频谱更为严重 比由于侧面变化而预期的。项目2将研究表观遗传机制 调节BHLH转录因子手1，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。这些研究是基于安东尼·菲鲁利（Anthony Firulli）博士的实验室和 将检验总体假设，即手部的表观遗传调节指导正常心肌细胞 图案。其他研究将确定手1的DNA占用率和相互作用的转录伙伴，因此 建立调节左心室，乳头状肌肉和CCS形态发生的基因调节网络。 项目3将研究对中胚层规格和心源分化至关重要的表观遗传机制。 这些研究以Weinian Shou博士的实验室的工作为基础，将检验总体假设 赖氨酸甲基转移酶SMYD4调节组蛋白修饰对于建立正确数量的正确数量 CPCS。项目4将研究一种新型平面细胞极性效应蛋白Shroom3在发病机理中的作用 CHD。这些研究以马修·杜宾博士的实验室的工作为基础，并将检验总体假设 该shroom3在PCP途径内的许多要点相互作用，并且确定了罕见的CHD患者 - 特定的Shroom3变体破坏心肌细胞中的PCP。拟议的工作将由 参与三个核心（核心A - 给药；核心B-胚胎干细胞的生长和遗传学 修改模型；和核心C-心脏生理和成像）。最终，该计划提出的研究 项目授予应用程序将说明表观遗传，转录和信号传导机制如何发生 心脏祖细胞和胚胎心肌细胞都建立了必要的基因调节网络 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提供信息 旨在减轻CHD的有害影响。