Type beta transforming growth factor (TGFbeta) and related cytokines including bone morphogenic proteins (BMPs) have bone implicated in diverse aspects of cardiovascular development, dysfunction, and disease including cardiac myogenesis itself, and establishment of the body axes. At present, this case is largely contingent on extrapolation from avian explants and other heterologous model systems. The application of mouse genetics to TGFbeta signaling in vivo has been confounded both by the extensive redundancy among family members, and by maternal rescue (transplacental delivery). Signal transduction for TGFbeta family members involves paired membrane-spanning serine-threonine kinases: type II receptors bind ligand with high affinity, then phosphorylate the type I receptors (activin receptor-like kinases, or ALK proteins), which mediate the downstream effects. Two proposed pathways for TGFbeta and BMP receptor signaling involve the TGFbeta/BMP-activated kinase, and Smad transcription factors; however, it is unknown whether these operate in series or in parallel (i.e., for different subsets of effects). Recently, we have developed a constitutively activated form of the type I receptor, ALK5, directed its expression to the embryonic myocardium, and shown that constitutive signaling by ALK5 arrests looping morphogenesis in mice.
Specific Aims of the present project are: . Using conditional activation of the embryonic-lethal ALK5 gene, to study molecular mechanisms for the block to looping morphogenesis. . To test the functional role of TAK and Smad proteins in signaling by ALK5, in vitro and in vivo. . Using cardiac-restricted expression or conditional induction of Cre recombinase, to test the function of endogenous ALK5 and ALK3 in the early mouse heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL049953-09
Application #
6449408
Study Section
Project Start
2001-05-01
Project End
2002-04-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
9
Fiscal Year
2001
Total Cost
$175,153
Indirect Cost
Name
Baylor College of Medicine
Department
Type
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Liu, Yu; Kaneda, Ruri; Leja, Thomas W et al. (2014) Hhex and Cer1 mediate the Sox17 pathway for cardiac mesoderm formation in embryonic stem cells. Stem Cells 32:1515-26
Zeve, Daniel; Seo, Jin; Suh, Jae Myoung et al. (2012) Wnt signaling activation in adipose progenitors promotes insulin-independent muscle glucose uptake. Cell Metab 15:492-504
Verzi, Michael P; Stanfel, Monique N; Moses, Kelvin A et al. (2009) Role of the homeodomain transcription factor Bapx1 in mouse distal stomach development. Gastroenterology 136:1701-10
Shah, Viraj R; Koster, Maranke I; Roop, Dennis R et al. (2007) Double-inducible gene activation system for caspase 3 and 9 in epidermis. Genesis 45:194-9
Niu, Zhivy; Li, Ankang; Zhang, Shu X et al. (2007) Serum response factor micromanaging cardiogenesis. Curr Opin Cell Biol 19:618-27
Chang, Jiang; Xie, Min; Shah, Viraj R et al. (2006) Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosis. Proc Natl Acad Sci U S A 103:14495-500
Zhang, Ying-Min; Bo, Jacqueline; Taffet, George E et al. (2006) Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosis. FASEB J 20:916-25
Ilagan, Roger; Abu-Issa, Radwan; Brown, Doris et al. (2006) Fgf8 is required for anterior heart field development. Development 133:2435-45
Zhang, Shu Xing; Garcia-Gras, Eduardo; Wycuff, Diane R et al. (2005) Identification of direct serum-response factor gene targets during Me2SO-induced P19 cardiac cell differentiation. J Biol Chem 280:19115-26
Vlahopoulos, Spiros; Zimmer, Warren E; Jenster, Guido et al. (2005) Recruitment of the androgen receptor via serum response factor facilitates expression of a myogenic gene. J Biol Chem 280:7786-92

Showing the most recent 10 out of 70 publications