Molecular regulation of ventricular maturation

摘要 先天性心脏病是人类出生缺陷中最常见的类型，其中许多疾病 在发育过程中出现的结构异常。为了满足日益增长的生理需求， 为了满足不断生长的胚胎的需求，发育中的心脏经历了复杂的形态发生变化， 它的心室肌结构更有效的收缩。这项建议的重点是心室成熟 其特征在于形成称为心脏小梁的肌肉突起及其随后的 扩张.我们的前期研究表明，心脏小梁形成是由定向心肌细胞启动的， 从致密层迁移，ErbB2细胞自主调节这一过程。上游 ErbB2，初级纤毛介导的流量传感是小梁形成所需的，通过其在激活Notch中的作用 心室内膜的信号。然而，仍有几个悬而未决的问题有待解决， 包括与1）调节ErbB2下游CM脱层的分子机制相关的那些 信号和2）推定的ErbB2配体Nrg1在心室形态发生中的确切功能。建立在我们 根据令人兴奋的初步数据，我们提出了以下具体目标来解决这些问题：目标1。到 表征促进小梁启动的心内膜和心肌信号。目标2。表征 Nrg1在心脏神经支配和小梁扩张中的作用。该提案的成功完成将 定义心室成熟的分子和细胞机制。我们的研究还将提供 新的洞察心脏神经支配在心室小梁扩张中的作用，从而阐明了新的 调节心脏形态发生和模式的范例。

Abstract Congenital heart diseases are the most common type of human birth defects, and many of these diseases feature structural abnormalities that emerge during development. In order to meet an increasing physiological demand of the growing embryo, the developing heart undergoes complex morphogenetic changes to optimize its ventricular myoarchitecture for more efficient contraction. This proposal is focused on ventricular maturation that is characterized by the formation of muscular protrusions called cardiac trabeculae and their subsequent expansion. Our prior studies revealed that cardiac trabeculation is initiated by directional cardiomyocyte migration from the compact layer, and that ErbB2 cell-autonomously regulates this process. Upstream of ErbB2, primary cilia mediated flow sensing is required for trabeculation through its role in activating Notch signaling in the ventricular endocardium. However, several outstanding questions remain to be addressed, including those related to 1) the molecular mechanism that regulates CM delamination downstream of ErbB2 signaling and 2) the exact function of the putative ErbB2 ligand Nrg1 in ventricular morphogenesis. Built on our exciting preliminary data, we propose the following specific aims to address these questions: Aim 1. To characterize endocardial and myocardial signals that promote trabecular initiation. Aim2. To characterize the role of Nrg1 in cardiac innervation and trabecular expansion. The successful completion of this proposal will define the molecular and cellular mechanisms of ventricular maturation. Our proposed study will also provide novel insight into the roles of cardiac innervation in ventricular trabecular expansion, thereby illuminating new paradigms for the regulation of cardiac morphogenesis and patterning.