Morphogenesis and growth of the ventricular wall in development and disease

摘要 先天性心脏病（CHD）是最常见的出生缺陷， 1 000个活产婴儿。在许多情况下，需要进行挽救生命的手术干预。尽管流行，在许多 例CHD的潜在分子病因学尚不清楚。本项目的核心主题 基金申请是为了阐明在脑缺血过程中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 规范和分化，如何妊娠中期事件影响分隔和乳头肌 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 为实现这些目标而提出的。项目1将研究有助于起源的分子机制 在X-连锁异位症动物模型中的CHD。这些研究建立在斯蒂芬妮·韦尔博士的工作基础上。 实验室，并将测试整体假设，即早期胚胎结构的形态发生缺陷， 影响原始祖细胞的迁移和分化，随后引起 心肌这种机制可以解释为什么在异位症患者中遇到的CHD谱 比预期的改变侧性的结果更严重。项目2将研究 调节心室分隔和乳头肌形成的分子机制。这些研究建立在 安东尼·菲鲁利博士实验室的工作，并将测试表达心肌细胞的整体假设， 转录因子赋予形态发生线索，指导发育中左心室的正常心肌细胞模式 心室，并且这种模式的妊娠中期改变引起CHD。这种机制将 建立调节心室正常和异常发育的细胞和分子通路 隔膜和乳头肌。项目3将研究调节左心室致密化的分子机制。 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， 此外，将剖析分子调控级联所需的建立正常的 心肌细胞极性这种机制将建立一种共同的潜在分子病因学， 导致左心室致密化不全拟议的工作将由三个小组的参与提供便利。 核心（管理、心脏成像和小鼠资源）。最终，本研究中提出的研究 计划项目补助金申请将说明如何事件发生之前，明显的心脏形成， 心脏发育早期和心室壁成熟晚期依次整合， 正常的心脏形态发生重要的是，确定这些事件的分子调控将提供 深入了解旨在减轻CHD有害影响的潜在干预措施。

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.