The primary goal of this proposal is to train the principal investigator to become an independent physician-scientist in the field of cardiac stem cell and regenerative biology. He proposes a detailed program of career development and a research plan involving human embryonic stem cell (hESC) derived cardiomyocytes. The training plan includes coursework, conferences, specialized instruction, and formation of an advisory committee to foster career development as a physician-scientist. In preliminary experiments, we demonstrated that grafting of hESC-derived cardiomyocytes into both uninjured and infracted hearts of immunodeficient rats produced human myocardium in vivo. Parallel in vitro work has identified highly promising strategies for deriving enriched cultures of human embryonic cardiomyocytes. The candidate exploits opportunities presented by this work in proposing the following specific aims: 1) optimize implants of hESC-derived myocardium in the infracted rat heart and determine whether this results in improved mechanical function;2) to test the hypothesis that hESC-derived cardiomyocyte grafts will show electromechanical coupling with the adjacent host myocardium;3) to test the hypothesis that with in vivo maturation, grafted hESC-derived myocardium will show phenotypic alterations in excitation-contraction coupling;and 4) develop strategies for the purification and/or induced differentiation of specialized cardiac conduction system cells from hESC-derived cardiomyocytes. The University of Washington represents an outstanding environment both for such studies and for the development of physician-scientists, a situation will be further enhanced through an institutional commitment to establish a Center for Cardiovascular &Regenerative Medicine. Combined with the support of the present career award, this environment will allow the principal investigator to acquire the technical and critical thinking skills to commence a successful independent line of investigation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL080431-05
Application #
7643446
Study Section
Special Emphasis Panel (ZHL1-CSR-M (F2))
Program Officer
Carlson, Drew E
Project Start
2005-05-01
Project End
2010-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
5
Fiscal Year
2009
Total Cost
$125,577
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Shiba, Yuji; Filice, Dominic; Fernandes, Sarah et al. (2014) Electrical Integration of Human Embryonic Stem Cell-Derived Cardiomyocytes in a Guinea Pig Chronic Infarct Model. J Cardiovasc Pharmacol Ther 19:368-381
Lundy, Scott D; Zhu, Wei-Zhong; Regnier, Michael et al. (2013) Structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells. Stem Cells Dev 22:1991-2002
Shiba, Yuji; Fernandes, Sarah; Zhu, Wei-Zhong et al. (2012) Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature 489:322-5
Xu, Chunhui; Police, Shailaja; Hassanipour, Mohammad et al. (2011) Efficient generation and cryopreservation of cardiomyocytes derived from human embryonic stem cells. Regen Med 6:53-66
Zhu, Wei-Zhong; Van Biber, Benjamin; Laflamme, Michael A (2011) Methods for the derivation and use of cardiomyocytes from human pluripotent stem cells. Methods Mol Biol 767:419-31
Zhu, Wei-Zhong; Xie, Yiheng; Moyes, Kara White et al. (2010) Neuregulin/ErbB signaling regulates cardiac subtype specification in differentiating human embryonic stem cells. Circ Res 107:776-86
Zhu, Wei-Zhong; Hauch, Kip D; Xu, Chunhui et al. (2009) Human embryonic stem cells and cardiac repair. Transplant Rev (Orlando) 23:53-68
Zhu, Wei-Zhong; Santana, Luis F; Laflamme, Michael A (2009) Local control of excitation-contraction coupling in human embryonic stem cell-derived cardiomyocytes. PLoS One 4:e5407
Shiba, Yuji; Hauch, Kip D; Laflamme, Michael A (2009) Cardiac applications for human pluripotent stem cells. Curr Pharm Des 15:2791-806
Reinecke, Hans; Minami, Elina; Zhu, Wei-Zhong et al. (2008) Cardiogenic differentiation and transdifferentiation of progenitor cells. Circ Res 103:1058-71

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