The molecular mechanisms that control cell growth in the heart are especially intriguing from both a biological and clinical point of view. Cardiac myocytes irreversibly lose the ability to divide soon after birth, contributing to the limited capacity to regenerate functional muscle mass after myocardial infarction. Conversely, cardiac myocytes can be provoked to undergo hypertrophy by a hemodynamic load; thus, increased work is transduced to increased mass. Cellular oncogenes have been postulated to function in a regulatory cascade for transduction of growth signals and to control movement through the cell cycle and initiation of DNA synthesis. However, very little is presently known about either expression or function of cellular oncogenes in cardiac muscle. The goal of this proposal is to elucidate, at the molecular level, fundamental mechanisms that control the relative ability of cardiac myocytes to replicate DNA and divide, by examining (i) the perinatal loss of proliferative capacity, and (ii) the hypertrophic response to pressure overload, in rat cardiac myocytes. These investigations are focused on the respective contributions of the myc and ras genes. First, the investigators will analyze the DNA synthesis induced by growth factors in vivo, in relation to basal and inducible expression of cellular oncogenes, during cardiac myocyte development. Second, the investigators will characterize DNA synthesis induced by pressure overload in vivo, in relation to basal and inducible oncogene expression, during later cardiac development. Third, the investigators will test whether exogenous oncogene alleles or the proteins they encode can function as a surrogates for growth factors that rat cardiac myocytes normally require for DNA synthesis, and can overcome the age-related block to DNA synthesis during cardiac muscle development. The biology of cardiac growth control differs in essential ways from both """"""""senescence"""""""" in fibroblastic cells and """"""""commitment"""""""" in skeletal muscle, and therefore its molecular basis cannot be readily extrapolated from data in other systems. Taken together the studies proposed here will test the hypothesis that cardiac growth control involves transduction of growth factors signals by ras and myc proteins, and will determine whether events proximal or distal can account for the loss of proliferative capacity during cardiac myocyte development.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL039141-04
Application #
3355760
Study Section
Molecular Cytology Study Section (CTY)
Project Start
1988-04-01
Project End
1993-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Schneider, M D; Brand, T (1995) Molecular analysis of TGF beta signal transduction. Dominant-inhibitory mutations of the type II and type I TGF beta receptor. Ann N Y Acad Sci 752:309-16
Abdellatif, M; MacLellan, W R; Schneider, M D (1994) p21 Ras as a governor of global gene expression. J Biol Chem 269:15423-6
MacLellan, W R; Lee, T C; Schwartz, R J et al. (1994) Transforming growth factor-beta response elements of the skeletal alpha-actin gene. Combinatorial action of serum response factor, YY1, and the SV40 enhancer-binding protein, TEF-1. J Biol Chem 269:16754-60
Schneider, M D; Kirshenbaum, L A; Brand, T et al. (1994) Control of cardiac gene transcription by fibroblast growth factors. Mol Reprod Dev 39:112-7
Schneider, M D; MacLellan, W R; Kirshenbaum, L A et al. (1994) Molecular approaches to cardiac development and hypertrophy. Tex Heart Inst J 21:2-5
Brand, T; MacLellan, W R; Schneider, M D (1993) A dominant-negative receptor for type beta transforming growth factors created by deletion of the kinase domain. J Biol Chem 268:11500-3
MacLellan, W R; Brand, T; Schneider, M D (1993) Transforming growth factor-beta in cardiac ontogeny and adaptation. Circ Res 73:783-91
Schneider, M D; French, B A (1993) The advent of adenovirus. Gene therapy for cardiovascular disease. Circulation 88:1937-42
Kirshenbaum, L A; MacLellan, W R; Mazur, W et al. (1993) Highly efficient gene transfer into adult ventricular myocytes by recombinant adenovirus. J Clin Invest 92:381-7
Parker, T G; Chow, K L; Schwartz, R J et al. (1992) Positive and negative control of the skeletal alpha-actin promoter in cardiac muscle. A proximal serum response element is sufficient for induction by basic fibroblast growth factor (FGF) but not for inhibition by acidic FGF. J Biol Chem 267:3343-50

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