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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Schramm, Charlene A
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University of North Carolina Chapel Hill
Chapel Hill
United States
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Battista, Nicholas A; Lane, Andrea N; Liu, Jiandong et al. (2018) Fluid dynamics in heart development: effects of hematocrit and trabeculation. Math Med Biol 35:493-516
Fleming, Nicole D; Samsa, Leigh A; Hassel, David et al. (2018) Rapamycin attenuates pathological hypertrophy caused by an absence of trabecular formation. Sci Rep 8:8584
Brown, Daniel; Samsa, Leigh Ann; Ito, Cade et al. (2018) Neuregulin-1 is essential for nerve plexus formation during cardiac maturation. J Cell Mol Med 22:2007-2017
Chrispell, Jared D; Dong, Enheng; Osawa, Shoji et al. (2018) Grk1b and Grk7a Both Contribute to the Recovery of the Isolated Cone Photoresponse in Larval Zebrafish. Invest Ophthalmol Vis Sci 59:5116-5124
Zhou, Yang; Wang, Li; Liu, Ziqing et al. (2017) Comparative Gene Expression Analyses Reveal Distinct Molecular Signatures between Differentially Reprogrammed Cardiomyocytes. Cell Rep 20:3014-3024
Liu, Ziqing; Wang, Li; Welch, Joshua D et al. (2017) Single-cell transcriptomics reconstructs fate conversion from fibroblast to cardiomyocyte. Nature 551:100-104
Liu, Ziqing; Chen, Olivia; Wall, J Blake Joseph et al. (2017) Systematic comparison of 2A peptides for cloning multi-genes in a polycistronic vector. Sci Rep 7:2193
Ma, Hong; Wang, Li; Liu, Jiandong et al. (2017) Direct Cardiac Reprogramming as a Novel Therapeutic Strategy for Treatment of Myocardial Infarction. Methods Mol Biol 1521:69-88
Samsa, Leigh Ann; Ito, Cade Ellis; Brown, Daniel Ross et al. (2016) IgG-Containing Isoforms of Neuregulin-1 Are Dispensable for Cardiac Trabeculation in Zebrafish. PLoS One 11:e0166734
Mouillesseaux, Kevin P; Wiley, David S; Saunders, Lauren M et al. (2016) Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6. Nat Commun 7:13247

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