The goal of the research is to define the inductive and patterning signals that specify the formation of cardiomyocytes in the embryo and to apply this information of the problem of cardiomyocyte regeneration. Preliminary data presented this application show that the secreted Wnt antagonists Dkk1 and Crescent are potent initiatory of Xenopus cardiogenesis in non-cardiogenic mesoderm. Additional results show that the cardiomyocyte differentiation is restricted to a portion of the heart/NKx2.5 field by suppressive signals from neurogenic tissue and by local cell-cell interactions mediated by Serrate and Notch. These signals, in conjunction with BMP, appear sufficient to promote cardiomyocyte differentiation in embryonic mesoderm. Three broad objectives are proposed. The first is to determine whether Wnt antagonists act directly on prospective cardiac progenitors or if they induce an intermediary factor in another tissue, such as the endoderm underlying the cardiac primordial. Although endoderm is essential for heart induction, the inducing proteins it produces are known. Therefore, a cDNA expression screen seeks to identify these factors from a dorsoanterior endoderm cDNA library. The second objective is to identify the type of neurogenic cells that restrict cardiomyocyte differentiation to the ventral portion of the Xenopus heart/Nkx2.5 field. Studies will then determine whether the neurogenic signal regulated cardiomyocyte differentiation through Notch and BMP signaling. Lastly, the third objective is to apply the knowledge of embryonic heart induction to cardiomyocyte regeneration. Experiments will assess the cardiomyogenic potency of a promising class of stem cells that are FACS purified from bone marrow and differentiated tissues. Factors that reside in the embryonic heart-forming region, such as Dkk1, Crescent and novel proteins secreted by the endoderm, will be tested for the ability to enhance myocardial differentiation of these cells in vivo.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059502-09
Application #
6924649
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Schramm, Charlene A
Project Start
1997-08-01
Project End
2006-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
9
Fiscal Year
2005
Total Cost
$240,000
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Mercola, Mark; Doevendans, Pieter (2012) Meeting review: cardiomyocyte regeneration and protection, La Jolla, California, June 2011. J Cardiovasc Transl Res 5:100-5
McKeithan, Wesley L; Colas, Alexandre R; Bushway, Paul J et al. (2012) Serum-free generation of multipotent mesoderm (Kdr+) progenitor cells in mouse embryonic stem cells for functional genomics screening. Curr Protoc Stem Cell Biol Chapter 1:Unit 1F.13
Willems, Erik; Cabral-Teixeira, Joaquim; Schade, Dennis et al. (2012) Small molecule-mediated TGF-? type II receptor degradation promotes cardiomyogenesis in embryonic stem cells. Cell Stem Cell 11:242-52
Schade, Dennis; Lanier, Marion; Willems, Erik et al. (2012) Synthesis and SAR of b-annulated 1,4-dihydropyridines define cardiomyogenic compounds as novel inhibitors of TGF? signaling. J Med Chem 55:9946-57
Lanier, Marion; Schade, Dennis; Willems, Erik et al. (2012) Wnt inhibition correlates with human embryonic stem cell cardiomyogenesis: a structure-activity relationship study based on inhibitors for the Wnt response. J Med Chem 55:697-708
Willems, Erik; Spiering, Sean; Davidovics, Herman et al. (2011) Small-molecule inhibitors of the Wnt pathway potently promote cardiomyocytes from human embryonic stem cell-derived mesoderm. Circ Res 109:360-4
Willems, Erik; Lanier, Marion; Forte, Elvira et al. (2011) A chemical biology approach to myocardial regeneration. J Cardiovasc Transl Res 4:340-50
Princen, Frederic; Bard, Emilie; Sheikh, Farah et al. (2009) Deletion of Shp2 tyrosine phosphatase in muscle leads to dilated cardiomyopathy, insulin resistance, and premature death. Mol Cell Biol 29:378-88
Foley, Ann C; Korol, Oksana; Timmer, Anjuli M et al. (2007) Multiple functions of Cerberus cooperate to induce heart downstream of Nodal. Dev Biol 303:57-65
Rutenberg, Joshua B; Fischer, Andreas; Jia, Haibo et al. (2006) Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors. Development 133:4381-90

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