This proposal describes a five-year career development program whose goal is to prepare Dr. Jiandong Liu for a role as an independent investigator. This program will promote his career development by providing expertise in molecular and developmental cardiac biology. The principal guidance will be provided by the mentor, Dr. Didier Stainier, Professor of Biochemistry & Biophysics at the University of California, San Francisco. He is an expert in cardiac development and has a long record of training independent scientists. The training plan includes structured mentorship with an advisory committee, formal coursework, and a research program which will provide thorough training in molecular and developmental cardiac biology. In his preliminary studies, Dr. Jiandong has developed and validated a set of tools to be used to study cardiac morphogenesis in zebrafish. He has used these tools to explore the role for hemodynamic and ErbB signaling in cardiac trabeculation, a critical morphogenetic process that optimizes the internal structure of the cardiac ventricle for efficient conduction and contraction. This work has demonstrated 1) that the initiation of trabeculation is regulated by blood flow in a process that likely requires Notch signaling, and 2) ErbB2 cell-autonomously regulates cardiomyocyte migration to form cardiac trabeculae. In the research proposal, Dr. Jiandong will build on these findings to test the hypotheses that (1) activation of Notch signaling by blood flow induces neuregulin1 (nrg1) expression in the endocardium, and (2) Nrg1 activates its ErbB receptors in the myocardium to initiate trabeculation by causing cardiomyocyte apical constriction. He will begin by carefully assessing cell architecture, cell shape changes and cell migration during cardiac trabeculation. He will then perform detailed functional studies to define the regulatory networks that link flow and shear stress to long-term structural changes in the heart, an area of fundamental importance for understanding both developmental disorders of heart formation as well as many forms of acquired heart disease. In addition, this work will provide a foundation for future studies on cardiac trabeculation to be carried out by Dr. Jiandong when he becomes an independent investigator.
Failure of trabecular formation or compaction during embryogenesis causes congenital cardiomyopathy, while 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 trabeculation to improve understanding of cardiac disease and facilitate the search for treatments.
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