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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL109079-04
Application #
8626437
Study Section
Special Emphasis Panel (NSS)
Program Officer
Schramm, Charlene A
Project Start
2011-08-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
4
Fiscal Year
2014
Total Cost
$224,100
Indirect Cost
$76,666
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Brown, Daniel R; Samsa, Leigh Ann; Qian, Li et al. (2016) Advances in the Study of Heart Development and Disease Using Zebrafish. J Cardiovasc Dev Dis 3:
Liu, Ziqing; Chen, Olivia; Zheng, Michael et al. (2016) Re-patterning of H3K27me3, H3K4me3 and DNA methylation during fibroblast conversion into induced cardiomyocytes. Stem Cell Res 16:507-18
Ma, Hong; Yin, Chaoying; Zhang, Yingao et al. (2016) ErbB2 is required for cardiomyocyte proliferation in murine neonatal hearts. Gene 592:325-30
Zhou, Yang; Wang, Li; Vaseghi, Haley Ruth et al. (2016) Bmi1 Is a Key Epigenetic Barrier to Direct Cardiac Reprogramming. Cell Stem Cell 18:382-95
Samsa, Leigh Ann; Fleming, Nicole; Magness, Scott et al. (2016) Isolation and Characterization of Single Cells from Zebrafish Embryos. J Vis Exp :
Vaseghi, Haley Ruth; Yin, Chaoying; Zhou, Yang et al. (2016) Generation of an inducible fibroblast cell line for studying direct cardiac reprogramming. Genesis 54:398-406
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
Samsa, Leigh Ann; Givens, Chris; Tzima, Eleni et al. (2015) Cardiac contraction activates endocardial Notch signaling to modulate chamber maturation in zebrafish. Development 142:4080-91
Wang, Li; Liu, Ziqing; Yin, Chaoying et al. (2015) Stoichiometry of Gata4, Mef2c, and Tbx5 influences the efficiency and quality of induced cardiac myocyte reprogramming. Circ Res 116:237-44
Wang, Li; Liu, Ziqing; Yin, Chaoying et al. (2015) Improved Generation of Induced Cardiomyocytes Using a Polycistronic Construct Expressing Optimal Ratio of Gata4, Mef2c and Tbx5. J Vis Exp :

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