The Principal Investigator and others have shown that cardiomyocytes produce growth factor (GF) peptides & express GF-receptors (GFRs) that temporally correlate with growth & maturation of myocytes, vascular angiogenesis, and ventricular ECM biosynthesis in the heart. One GF family of ligands and receptors found in cardiomyocytes with such diverse bioactivities is the transforming growth factor-beta (TGF-beta). Data gathered in the first funding period has led them to postulate that cardiomyocyte- derived TGF-beta function to coordinately regulate heart development in autocrine and paracrine mechanisms that are active in a continuum. Cardiomyocyte derived TGF-beta may influence final myocyte cell number and maturation (autocrine) as well as concomitant ventricular remodeling by way of non-myocyte growth and differentiation (paracrine) in the late fetal-to-mature heart. In the rat model system, our results will clarify & confirm TGF-beta based autocrine paradigms, as well as increase our understanding of TGF-beta role(s) in heart growth and maturation with pathophysiological implications.
Specific Aim 1 A, they will elucidate the differences in the cell surface and mRNA expression for the Type I, II, and III TGF-beta receptors TGF- betaR) to specific cell types and ventricular regions at important developmental periods in the rat (Late fetal, 1-3 days, and l-,2-,3-,5- ,7- and 9-weeks of age).
Specific Aim 1 B: they will determine when, at the above ages, the rat ventricle or regions contains biologically active TGF-beta. Primary myocyte conditioned media will be used to test for its postulate:d cardiomyocyte origin. Autocrine modulation of cardiomyocyte or myocyte cell line proliferation & expression of muscle-specific isoforms will be the indices of TGF-beta actions.
Specific Aim 2 asks if TGF-beta autocrine-mediated regulation of cardiomyocyte growth and phenotype is via the Type II TGF-betaR. We will test whether TGF- beta-induced changes in muscle specific isoform expression are eliminated by dominant negative disruptions of Type II TGF-beta receptor signalling in cardiomyocyte cell lines. The data generated in this continuation proposal will enhance our understanding of regional & temporal changes in the TGF-beta family that contribute to the development of the myocardium. They will also provide new insights into the regulatory pathways associated with myocyte responses to TGF-beta-mediated control of postnatal proliferation and maturational cellular phenotypic changes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL042218-08
Application #
2445179
Study Section
Special Emphasis Panel (ZRG2-HED-2 (01))
Project Start
1988-09-30
Project End
2000-06-30
Budget Start
1997-08-25
Budget End
2000-06-30
Support Year
8
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Loyola University Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
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Engelmann, G L; Campbell, S E; Rakusan, K (1996) Immediate postnatal rat heart development modified by abdominal aortic banding: analysis of gene expression. Mol Cell Biochem 163-164:47-56
Fatayerji, N; Engelmann, G L; Myers, T et al. (1996) In utero exposure to ethanol alters mRNA for insulin-like growth factors and insulin-like growth factor-binding proteins in placenta and lung of fetal rats. Alcohol Clin Exp Res 20:94-100
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Engelmann, G L; Grutkoski, P S (1994) Coordinate TGF-beta receptor gene expression during rat heart development. Cell Mol Biol Res 40:93-104
Engelmann, G L; Dionne, C A; Jaye, M C (1993) Acidic fibroblast growth factor and heart development. Role in myocyte proliferation and capillary angiogenesis. Circ Res 72:7-19
Engelmann, G L; Birchenall-Roberts, M C; Ruscetti, F W et al. (1993) Formation of fetal rat cardiac cell clones by retroviral transformation: retention of select myocyte characteristics. J Mol Cell Cardiol 25:197-213
Engelmann, G L (1993) Coordinate gene expression during neonatal rat heart development. A possible role for the myocyte in extracellular matrix biogenesis and capillary angiogenesis. Cardiovasc Res 27:1598-605
Eleftheriades, E G; Durand, J B; Ferguson, A G et al. (1993) Regulation of procollagen metabolism in the pressure-overloaded rat heart. J Clin Invest 91:1113-22
Engelmann, G L; Boehm, K D; Birchenall-Roberts, M C et al. (1992) Transforming growth factor-beta 1 in heart development. Mech Dev 38:85-97

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