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.
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