CELLULAR RECOGNITION AND CARDIAC MORPHOGENESIS

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The dramatic cellular changes that take place during heart development are the result of the expression and interaction of several morphogenetic factors. At critical times in heart development, such as looping, septation, trabeculation, and valve formation, these factors play a significant role in determining the form and function of the developing heart. Fundamental events necessary for heart development include the expression of extracellular matrix (ECM) components, arrangement and remodeling of ECM, attachment of the ECM to cellular components, and the formation of cell:cell contacts. The proposed investigations will focus on the interaction between ECM components and specific cell surface receptors of the differentiating cellular components of the heart. Specifically we will examine: 1) the expression of integrins and cadherins at different stages of heart development; 2) the expression of basement membrane components during development by cardiac myocytes and their possible role in differentiation of the heart; and 3) the role of growth factors/cytokines on the regulation of integrins, cadherins and collagenases during cardiac development. Several experimental approaches will be used to analyze these specific aims including: A) 3-dimensional collagen gel cultures to examine the effects of growth factors/cytokines on expression of ECM components, their specific receptors and metalloproteases; B) cell migration, cell-cell interaction with aggregate formation in rotation culture, and cell:ECM adhesion assays to determine the role of potential regulatory components; C) microinjection of whole embryo cultures and individual cells to determine the effects of regulatory components at specific stages of development; D) morphological and morphometric analysis of immunolocalization of specific regulatory components and their receptors during critical stages of development; and E) analysis of the biochemical and molecular expression of regulatory components in collagen gels, embryo culture compared to in vivo development. These experimental approaches will allow for the analysis of the regulation of the morphogenetic events associated with normal heart development and provide essential data on the mechanisms involved in congenital heart defects.