and Specific Aims.) Cell-cell and cell-extracellular matrix interactions are important for cell positioning and differentiation during development and for targeting immune cells to sites of inflammation in the adult. Such processes are clearly important for the development of multicellular organ such as lung, and for the ability to mount an inflammatory response in the lung. Integrins are a families of adhesion receptors that are involved in such processes. The integrin, a5b1, and its extracellular matrix protein ligand, fibronectin (FN), are expressed in a developmentally regulated fashion in lung, and reagents that block their interaction inhibit lung development. These adhesion molecules then appear to be re-expressed in response to fibrotic disease in the lung. A second integrin fibronectin receptor, a4b1, binds to a unique region of fibronectin that is alternatively spliced in fibronectin mRNA during development. In addition to fibronectin, a4b1 has a second ligand, vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 was first identified as a protein that appears on the surface of endothelial cells in response to inflammation, and its interaction with a4b1 on immune cells is important for targeting these cells to activated endothelium. Therefore, the a4b1/VCAM-1 interaction is important for mounting an inflammatory response in lung. These receptors have a second role: They mediate cell-cell interactions that are important in development, particularly, in skeletal muscle differentiation. The application proposes to test the possibility that expression of a4b1 and VCAM- 1 is developmentally regulated in lung by using reagents that block a4b1/VCAM- 1 interactions lung explant cultures.
The Specific Aims are to:1) examine molecular mechanisms controlling the pattern of VCAM-1 on endothelial cells and the integrin a4 on immune cells in culture; and 2) identify and characterize elements in the FN, a5, a4, and VCAM-1 gene promoters that are responsible for expression in developing lung, and for re-expression in the adult lung in response to inflammation and disease.
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