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: 9208530
• 负责人: Anthony B. Firulli
• 金额: $ 236.59万
• 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 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9208530
• 关键词: Address; Affect; Animal Model; Animals; Appearance; Applications Grants; Area; BHLH Protein; Cardiac; Cardiac Myocytes; Cardiac development; Cardiomyopathies; Cell Polarity; Cells; Child; Clinical; Congenital Abnormality; Congenital Heart Defects; Congenital cardiomyopathy; Cues; Defect; Development; Disease; Embryo; Embryonic Structures; Environment; Etiology; Event; Exhibits; Family member; Fingers; Generations; Genetic Transcription; Growth; Health; Heart Ventricle; Helix-Turn-Helix Motifs; Human; Intervention; Intraventricular; Knowledge; Laboratories; Left; Left ventricular non-compaction; Left ventricular structure; Life; Link; Live Birth; Mesoderm; Methodology; Mission; Molecular; Morphogenesis; Mus; Muscle; Mutate; Mutation; Myocardium; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Phenocopy; Population; Porifera; Pregnancy; Prevalence; Prevention; Primitive Streaks; Process; Production; Program Research Project Grants; Public Health; Reagent; Regulation; Research; Research Proposals; Resources; Role; Sarcomeres; Savings; Signal Transduction; Situs Inversus; Standardization; Stem cells; Structure; Testing; Thinness; Ultrasonography; United States; United States National Institutes of Health; Ventricular; Ventricular Septal Defects; Work; base; cardiogenesis; cardiovascular visualization; gastrulation; human disease; insight; migration; mouse model; papillary muscle; public health relevance; transcription factor

ABSTRACT Congenital heart defects (CHDs) are the most commonly encountered birth defect, affecting as many as 8 in 1,000 live births. In many cases, life-saving surgical intervention is required. Despite the prevalence, in many cases the underlying molecular etiology of CHDs is not 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 objective is to gain understanding of how early events impacting mesoderm-lineage specification and differentiation, how mid-gestational events impacting septation and papillary muscle formation, and how late-gestational events impacting cardiomyocyte polarity and sarcomere maturation each contribute to normal ventricular morphogenesis. Three highly interactive and complementary Projects are proposed to attain these objectives. Project 1 will study the molecular mechanisms contributing to the genesis of CHDs in an animal model of X-linked heterotaxy. These studies build on work from Dr. Stephanie Ware's laboratory and will test the overall hypothesis that morphogenic defects in early embryonic structures can impact the migration and differentiation of primitive progenitor cells which subsequently give rise to the myocardium. Such a mechanism would explain why the spectrum of CHDs encountered in heterotaxia patients is more severe than what would be anticipated to result from altered sidedness. Project 2 will study the molecular mechanisms regulating ventricular septation and papillary muscle formation. These studies build on work from Dr. Anthony Firulli's laboratory and will test the overall hypothesis that expression cardiomyogenic transcription factors imparts morphogenic cues directing normal cardiomyocyte patterning in the developing left ventricle, and that mid-gestational alteration of this patterning gives rise to CHD. Such a mechanism would establish cell and molecular pathways which regulate normal and abnormal development of the ventricular septation and papillary muscle. Project 3 will study the molecular mechanisms regulating compaction of the left ventricle during cardiac development. These studies build on work from Dr. Weinian Shou's laboratory and will test the overall hypothesis that altered cardiomyocyte cell polarity gives rise to ventricular noncompaction, and furthermore, will dissect the molecular regulatory cascades which are required to establish normal cardiomyocyte polarity. Such a mechanism would establish a common underlying molecular etiology which gives rise to left ventricular noncompaction. The proposed work will be facilitated by the participation of three cores (Administration, Cardiac Imaging and Mouse Resources). Ultimately, the studies proposed in this Program Project Grant application will illustrate how events occurring prior to overt heart formation, during early cardiac development, and during late maturation of the ventricular wall are sequentially integrated for normal cardiac morphogenesis. Importantly, defining the molecular regulation of these events will provide insight into potential interventions aiming to mitigate the deleterious impact of CHD.

抽象的 先天性心脏病 (CHD) 是最常见的出生缺陷，影响多达 8 名儿童 1,000 名活产婴儿。在许多情况下，需要进行挽救生命的手术干预。尽管流行，但在许多 CHD 的潜在分子病因学尚不清楚。本计划项目的中心主题 拨款申请旨在阐明调节心室生长和形态发生的机制 发展。我们的目标是了解早期事件如何影响中胚层谱系 规格和分化，妊娠中期事件如何影响分隔和乳头肌 形成，以及妊娠晚期事件如何影响心肌细胞极性和肌节成熟 有助于正常的心室形态发生。三个高度互动和互补的项目是 建议实现这些目标。项目1将研究有助于起源的分子机制 X连锁异位动物模型中的CHD。这些研究以 Stephanie Ware 博士的工作为基础 实验室并将测试早期胚胎结构的形态发生缺陷可以 影响原始祖细胞的迁移和分化，从而产生 心肌。这种机制可以解释为什么异位症患者会遇到一系列先心病 比改变侧面所预期的结果更严重。项目2将研究 调节室间隔和乳头肌形成的分子机制。这些研究建立在 Anthony Firulli 博士实验室的工作将测试表达心肌源性的总体假设 转录因子赋予形态发生线索，指导发育中的左心肌细胞的正常模式 心室，妊娠中期这种模式的改变会引起冠心病。这样的机制将 建立调节心室正常和异常发育的细胞和分子途径 分隔和乳头肌。项目3将研究调节左侧紧致度的分子机制 心脏发育过程中的心室。这些研究建立在寿伟年博士实验室的工作基础上，并将 检验心肌细胞极性改变导致心室致密化不全的总体假设，以及 此外，将剖析建立正常状态所需的分子调控级联 心肌细胞极性。这种机制将建立一个共同的潜在分子病因学 引起左心室致密化不全。三人的参与将促进拟议的工作 核心（管理、心脏成像和鼠标资源）。最终，本研究中提出的研究 计划项目拨款申请将说明在明显的心脏形成之前、期间如何发生事件 早期心脏发育和心室壁晚期成熟过程依次整合 正常的心脏形态发生。重要的是，定义这些事件的分子调控将提供 深入了解旨在减轻冠心病有害影响的潜在干预措施。