Cardiomyocyte Proliferation and Ventricular Morphogenesis

描述(由申请者提供)：这个项目解决了在小鼠胚胎发育过程中负责形成心室室的机制。我们提出了一种模型，在该模型中，心外膜分泌的信号促进了致密区下心肌的细胞分裂和形态组织。在本申请中，我们建议追求以下目标：具体目标1：确定IGF信号在心脏发育中的作用。这一建议中提出的几条证据表明，IGF信号是中期心脏增殖的重要中介，尽管之前还没有研究过IGF信号在心脏发育中的功能作用。为此，我们将首先对IGF配体和受体发生常规和条件性突变的小鼠胚胎进行表型评估。具体目的2：明确在心外膜和心内膜的影响下，致密心肌和小梁心肌形态发生分化的途径。心外膜和心内膜因子汇聚在一组共同的信号中间产物上，以激活增殖，但又不同，以实现不同的形态发生结果。心肌如何被分割成致密的和松弛的间隔是心脏发育的一个关键方面，但目前还不是很清楚。在这一目标中，我们讨论了导致致密区或小梁心肌中基因选择性表达的分子途径，考虑到这些是致密区与小梁形态发生的更大生物学过程的替代标记。与公共健康相关：这个项目考虑胚胎心脏的肌肉是如何形成和组织起来的。对这些过程的了解可能会让我们深入了解某些形式的先天性心脏缺陷，并可能与逆转或治疗成人心力衰竭病理的治疗相关。

DESCRIPTION (provided by applicant): This project addresses mechanisms that are responsible for formation of the ventricular chamber of the heart during mouse embryonic development. We have advanced a model in which signals secreted from the epicardium promote cell division and morphological organization of the underlying compact zone myocardium. In this application, we propose to pursue the following goals: Specific Aim 1: To define the role of IGF signaling in heart development. Several lines of evidence presented in this proposal indicate that IGF signaling is an important mediator of proliferation in the midgestation heart, although a functional role for IGF signaling in heart development has not been examined previously. In this Aim, we will primarily undertake a phenotypic assessment of mouse embryos in which IGF ligands and receptors are conventionally and conditionally mutated. Specific Aim 2: To define pathways that lead to morphogenic differentiation of the compact and trabecular myocardium under the influence of the epicardium and endocardium. Epicardial and endocardial factors converge on a common set of signaling intermediates to activate proliferation, yet diverge to achieve differential morphogenic outcomes. How the ventricular myocardium becomes partitioned into compact and trabecular compartments is a critical aspect of heart development, yet one that is not well- understood. In this Aim, we address the molecular pathways that result in the selective expression of genes in the compact zone or trabecular myocardium, with the consideration that these are surrogate markers for the larger biological processes of compact vs. trabecular morphogenesis. PUBLIC HEALTH RELEVANCE: This project considers how the muscle of the embryonic heart forms and becomes organized. An understanding of these processes may give insight into certain forms of congenital heart defects, and may be relevant to therapies to reverse or treat the pathology of adult heart failure.