Understanding how the urothelium grows and differentiates is central to understanding a number of bladder diseases. Being able to modulate these processes would allow us to improve treatment of urinary tract abnormalities in children and adults. Preliminary evidence in our laboratory suggests that Fibroblast Growth Factor (FGF)-10 plays an important role in regulating DNA synthesis of urothelial cells, a crucial process involved in control of growth, differentiation, and repair of the urothelium. This process is described by a complex network of paracrine action that originates in the mesenchyme but acts on the urothelium. Disruption of this process in FGF10-null mice alters the differentiation of bladder urothelial cells and results in an abnormal transitional epithelium typified by incomplete stratification. Other processes involved in the control of growth and differentiation of the urothelium include cytokines and growth factors of various types. We propose to attack the FGF-10 part of these processes because a) nothing is known about the biology of FGF-10 in the bladder and b) an understanding of how FGF-10 works in conjunction with these other processes will allow us to develop new and innovative methods to strengthen our translational approach to the problem of bladder and urinary tract disease. In order to achieve these goals, we have established specific aims for this period of support to better understand how FGF-10 functions in the context of a dynamic steady-state interrelationship that stimulates the progression of the urothelial cell cycle. Two mechanisms for how FGF-10 triggers proliferation are hypothesized: 1) the translocation of FGF-10 into urothelial cell nuclei and 2) a signalling cascade that begins with the heparin-dependent phosphorylation of tyrosine residues of surface receptors. We propose that negligible levels of FGF-10 define the normal urothelial phenotype -that of quiescence. During proliferative phases, levels of FGF-10 rise at the urothelial cell surface and/or within urothelial cell nuclei. Since our preparations of recombinant FGF-10 induce urothelial cell proliferation in animals, we eventually plan to evaluate the feasiblity of FGF-10 therapy in repairing the urothelium in clinical settings such as urethral trauma stricture disease and trauma. This study of the basic mechanisms of action will set the stage for later clinical use. ? ?
