The subject of this research concerns elucidating the molecular basis for Cell Surface:ECM interactions during early cardiac morphogenesis. Specifically, we propose to study an embryonic chicken and mouse cell surface protein described herein, and its physical interaction with collagen. We predict that these partially characterized collagen binding proteins (CBP) are part of an intergral membrane protein complex that mediates cell surface:collagen interactions during heart development. In order to test this prediction the studies proposed below will: 1) Examine in more detail the physical characteristics of CBP. 2) Investigate the subunit structure of CBP by use of monoclonal antibodies. 3) Investigate by direct experimentation the role collagen and CBP play in differentiation and morphogenesis of precardiac mesoderm. 4) Examine the behavior of ventricular endothelium versus cushion endothelium when the cells are cultured in the presence of various antibodies and synthetic peptides. 5) Examine the relationship between cell:ECM interactions and the acquisition of specific physiological properties (contractility, ionic coupling, membrane excitability). 6) Use gene cloning technology in order to prepare cDNA to CBP. 7) Employ the cDNAs in studies of CBP gene expression and CBP primary sequence, and as a means of producing biochemical amounts of pure CBP. In addition to contributing to our understanding of early vertebrate morphogenesis it is conceivable that these studies could help illuminate some of the fundamental mechanisms responsible for cardiac malformations. A very large proportion of cardiac birth defects are attributable to structures that receive contributions from endocardial cushions. In this proposal we describe studies concerning the morphogenesis of these important primordia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL037709-04
Application #
3353645
Study Section
(SRC)
Project Start
1986-09-30
Project End
1991-09-29
Budget Start
1989-09-30
Budget End
1990-09-29
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Hungerford, J E; Owens, G K; Argraves, W S et al. (1996) Development of the aortic vessel wall as defined by vascular smooth muscle and extracellular matrix markers. Dev Biol 178:375-92
Bouchey, D; Drake, C J; Wunsch, A M et al. (1996) Distribution of connective tissue proteins during development and neovascularization of the epicardium. Cardiovasc Res 31 Spec No:E104-15
Bouchey, D; Argraves, W S; Little, C D (1996) Fibulin-1, vitronectin, and fibronectin expression during avian cardiac valve and septa development. Anat Rec 244:540-51
Drake, C J; Little, C D (1995) Exogenous vascular endothelial growth factor induces malformed and hyperfused vessels during embryonic neovascularization. Proc Natl Acad Sci U S A 92:7657-61
Drake, C J; Cheresh, D A; Little, C D (1995) An antagonist of integrin alpha v beta 3 prevents maturation of blood vessels during embryonic neovascularization. J Cell Sci 108 ( Pt 7):2655-61
Wunsch, A M; Little, C D; Markwald, R R (1994) Cardiac endothelial heterogeneity defines valvular development as demonstrated by the diverse expression of JB3, an antigen of the endocardial cushion tissue. Dev Biol 165:585-601
Gallagher, B C; Sakai, L Y; Little, C D (1993) Fibrillin delineates the primary axis of the early avian embryo. Dev Dyn 196:70-8
Potts, A J; Little, C D (1992) Beta 1 integrins isolated from embryonic chicken fibroblasts bind to monomers and polymers of type I collagen. J Cell Physiol 152:558-67
Spence, S G; Argraves, W S; Walters, L et al. (1992) Fibulin is localized at sites of epithelial-mesenchymal transitions in the early avian embryo. Dev Biol 151:473-84
Drake, C J; Little, C D (1991) Integrins play an essential role in somite adhesion to the embryonic axis. Dev Biol 143:418-21

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