The interaction of epithelial cells with components of the extracellular matrix plays an essential role in the regulation of cell morphology, response to environmental growth factors, and differentiation. However, little is known about the mechanism of epithelial cell-matrix interaction. Studies performed with in vitro propagated fibroblastic and transformed cells revealed the presence of 140kD transmembrane glycoproteins with structural similarity to platelet and leukocyte adhesion receptors; this superfamily has now been termed the Integrin system. However, many non- Integrin type adhesion receptors have been described. Additionally, it appears that receptors are developmentally regulated suggesting that cells are capable of modulating the spectrum of receptors for matrix proteins during various stages of their life thus modifying their shape and adhesion. Highly differentiated epithelia of the renal corpuscle are critical to the normal filtering function of the kidney and these cells have developed unique basolateral connections to the underlying basement membrane. When the cells or basement membranes are altered in disease processes, this epithelium undergoes rapid phenotypic modulation leading to cell simplification, increased apposition of cell surfaces to the basement membrane, and functional abnormalities. The proposed studies will identify and study the in vivo and in vitro modulation of matrix receptors synthesized by glomerular and proximal tubule epithelial cells during morphogenesis, following pathologic injury, treatment with cytokines or transforming growth factor-beta, or upon in vitro propagation. Monoclonal antibodies will be produced against novel receptors and will be used to isolate and study these molecules. Structural data will be obtained by molecular biological techniques. Antibodies and peptides which block the adhesion of epithelia to extracellular matrix macromolecules will be used to induce perturbation of cell-matrix interactions in vitro and in vivo and the resultant functional and morphological alterations will be determined. These studies will provide detailed information on the interaction of renal epithelia with extracellular matrix components during their life cycle. This will augment our understanding of the sequence of events in renal pathologic conditions and help in the development of rational therapeutic strategies intended to abrogate the disease processes.
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