MOLECULAR BASIS AND MECHANISMS OF CYST ACTIVATING FACTOR

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Polycystic kidney disease (PKD) is a major cause of end-stage renal disease (ESRD). In the most common inherited form, autosomal dominant PKD, cysts are initiated by mutated genes that encode proteins (polycystins) that stimulate epithelial proliferation, fluid accumulation and extracellular matrix remodelling. Although all polycystic kidneys enlarge due to expanding cysts within them, only about 50% of patients develop ESRD. Evidence indicates that epigenetic factors have significant roles in determining the course of ADPKD. In a systematic search for potential "progression factors", a potent neutral lipid that stimulates epithelial cell proliferation, transepithelial fluid secretion and monocyte chemotaxis was recently identified in cyst fluids of patients with ADPKD. In view of these features this lipid or family of lipids has been named cyst activating factor (CAF). This project will test the hypothesis that CAP is a potent lipid product of renal cyst formation in ADPKD and functions as a progression factor that accelerates pathogenesis by increasing cellular proliferation, stimulating transpithelial fluid secretion, and promoting interstitial inflammation and fibrosis. The aims of this proposal are to: 1) Purify to homogeneity CAF from ADPKD cyst fluid and determine its molecular structure by appropriate analytical, biochemical, and biophysical techniques; 2) Explore the mechanisms by which CAF stimulates fluid transport in ADPKD cyst epithelial cells; 3) Delineate the mechanisms by which CAF stimulates cyst epithelial cell proliferation; 4) Investigate the effect of CAF on the interactions between ADPKD cyst epithelial cells and monocyte/macrophages and the role of matrix metalloproteinases and metalloproteinase inhibitors in this interaction. The achievement of these aims requires the application of techniques in analytical chemistry, cell biology, cell physiology, molecular biology and biochemistry. It is anticipated that the results will yield novel insights about a newly recognized renal lipid of specific importance to the pathogenesis of polycystic kidney disease.