Molecular regulation of ventricular maturation

摘要

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.