Molecular regulation of ventricular maturation

摘要 先天性心脏病是人类最常见的出生缺陷类型，其中许多疾病 以发展过程中出现的结构性异常为特征。为了满足日益增长的生理需求 发育中的胚胎需求，发育中的心脏经历复杂的形态发生变化来优化 它的心室肌结构可以更有效地收缩。这项建议的重点是心脏的成熟。 其特征是称为心脏小梁的肌肉突起的形成及其随后的 扩张。我们以前的研究表明，心脏小梁形成是由定向心肌细胞启动的 从致密层迁移，ErbB2细胞自主地调节这一过程。的上游 ERBB2，初级纤毛介导的流量感应是小梁形成所必需的，它通过激活Notch的作用 心内膜上的信号。然而，仍有几个悬而未决的问题需要解决， 包括与1)调节ErbB2下游CM分层的分子机制 2)ErbB2配体Nrg1在心室形态发生中的确切功能。建立在我们的 令人振奋的初步数据，我们提出了以下具体目标来解决这些问题：目标1。 描述促进骨小梁起始的心内膜和心肌信号。AIM2.要刻画 Nrg1在心脏神经支配和小梁扩张中的作用。这项提议的成功完成将 明确心室成熟的分子和细胞机制。我们建议的研究亦会提供 心脏神经支配在脑室小梁扩张中的作用的新见解，从而阐明了新的 心脏形态发生和构型调控的范例。

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.