PROTEINS AS SIGNALS IN UROTHELIAL CELL PROLIFERATION

了解尿路上皮如何生长和分化是了解许多膀胱的核心。 疾病。能够调节这些过程将使我们能够改进尿路的治疗 儿童和成人的异常。我们实验室的初步证据表明，成纤维细胞生长 成纤维细胞生长因子-10在调节尿路上皮细胞DNA合成中起重要作用，这是一个重要的过程 参与控制尿路上皮的生长、分化和修复。这个过程由一个 起源于间充质但作用于尿路上皮的旁分泌作用的复杂网络。 FGF10基因缺失小鼠这一过程的中断改变了膀胱尿路上皮细胞的分化和结果 在以不完全复层为代表的异常过渡上皮中。中涉及的其他进程 对尿路上皮生长和分化的调控包括各种细胞因子和生长因子。 我们建议攻击这些过程中的成纤维细胞生长因子-10部分，因为a)对 膀胱中的成纤维细胞生长因子-10，以及b)了解成纤维细胞生长因子-10如何与其他 流程将允许我们开发新的和创新的方法，以加强我们的翻译方法 膀胱和尿路疾病的问题。为了实现这些目标，我们建立了 本期支持的具体目标是更好地了解成纤维细胞生长因子-10在 刺激尿路上皮细胞周期进展的动态稳态相互关系。二 推测了成纤维细胞生长因子-10如何触发增殖的机制：1)成纤维细胞生长因子-10移位到 尿路上皮细胞核和2)开始于肝素依赖的磷酸化的信号级联。 表面受体的酪氨酸残基。我们认为，可以忽略不计的成纤维细胞生长因子-10水平定义了正常 尿路上皮表型--静止型。在增生期，尿路上皮成纤维细胞生长因子-10水平升高 细胞表面和/或尿路上皮细胞核内。由于我们制备的重组成纤维细胞生长因子-10诱导 在动物的尿路上皮细胞增殖，我们最终计划评估成纤维细胞生长因子-10治疗的可行性。 在临床环境下修复尿路上皮，如尿路创伤、狭窄、疾病和创伤。本研究 基本作用机制的研究将为以后的临床应用奠定基础。

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.