INTEGRINS AND THE PATHOGENESIS OF INTERSTITIAL CYSTITIS

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Interstitial cystitis (lC) is a chronic inflammatory disease of the urinary bladder. The etiology is obscure. One of the main diagnostic tools currently available for lC reveals the presence of glomerulations on cystoscopic examination. We propose that this and other symptoms associated with lC are indicative of aberrant ability for remodeling of the transitional epithelium, e.g. during micturition. The normal maintenance of tissue architecture involves the interaction of cells with extracellular matrix (ECM) and neighboring cells. Many of these interactions are mediated through integrins, a family of cell membrane ECM receptors. Integrins are of crucial importance in cell-cell signaling and in structural integrity at cell-cell junctions and cell-ECM interfaces. Based on preliminary studies in our laboratory, we propose the general hypothesis that dysregulation in expression, or spatial distribution, of specific integrins in bladder epithelial cells is an important etiological determinant of interstitial cystitis (lC). The main objective of the proposed studies is to investigate the role of integrins in cell-cell and cell-ECM interactions, and the regulation of their expression in urothelial cells. Epithelial cells we isolate from the human urinary bladder (UB) and human ureter (UT) will be studied using RNA analysis, immunoprecipitation studies, immunofluorescence microscopy, cell attachment and cell spreading assays, intracellular pH measurements by fluorescence spectroscopy, proliferation and differentiation assessment assays, with the following specific aims: (1) To investigate the constitutive expression of integrins involved in UB cell-cell contact and UB attachment to fibronectin (FN), collagen (CO), laminin (LN) and Matrigel; (2) To explore the possibility that transforming growth factor beta (TGFbeta and 17beta-estradiol regulate urothelial proliferation and differentiation by affecting integrin-mediated cell attachment, cell spreading or cell-cell contact; (3) To investigate whether ECM influences urothelial growth and differentiation by modulating intracellular signalling events via an integrin-mediated mechanism; (4) To investigate the possible influences of integrin expression and spatial distribution on phenotypic properties of urothelial cells from patients with lC and stress incontinence, including adhesion, production of FN, CO and LN, responsiveness to TGFbeta and 17beta-estradiol, differentiation and proliferation.