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.

Public Health Relevance

Congenital heart diseases, the most common type of human birth defect, frequently exhibit structural abnormalities including those arising from defective ventricular maturation. In many forms of acquired heart disease, the ventricle becomes adversely remodeled, with loss of normal ventricular trabecular structure and consequent deterioration of ventricular function. This proposal aims to delineate regulatory mechanisms underlying cardiac chamber morphogenesis to improve understanding of cardiac disease and facilitate the search for treatments.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56HL133081-01A1
Application #
9544360
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2017-09-15
Project End
2018-08-31
Budget Start
2017-09-15
Budget End
2018-08-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Battista, Nicholas A; Lane, Andrea N; Liu, Jiandong et al. (2017) Fluid dynamics in heart development: effects of hematocrit and trabeculation. Math Med Biol :
Brown, Daniel; Samsa, Leigh Ann; Ito, Cade et al. (2017) Neuregulin-1 is essential for nerve plexus formation during cardiac maturation. J Cell Mol Med :