PROTEINS AS SIGNALS IN UROTHELIAL CELL PROLIFERATION

描述（由申请人提供）：了解尿路上皮如何生长和分化是了解许多膀胱疾病的核心。能够调节这些过程将使我们能够改善儿童和成人尿路异常的治疗。我们实验室的初步证据表明，成纤维细胞生长因子(FGF)-10在调节尿路上皮细胞的DNA合成中起重要作用，这是一个控制尿路上皮生长、分化和修复的关键过程。这个过程是由一个复杂的旁分泌作用网络描述的，它起源于间质，但作用于尿路上皮。在fgf10缺失的小鼠中，这一过程的破坏改变了膀胱尿路上皮细胞的分化，并导致以不完全分层为特征的异常移行上皮。其他参与控制尿路上皮生长和分化的过程包括细胞因子和各种类型的生长因子。我们建议攻击这些过程中的FGF-10部分，因为a)对膀胱中FGF-10的生物学一无所知，b)了解FGF-10如何与这些其他过程结合工作将使我们能够开发新的创新方法，以加强我们对膀胱和尿路疾病问题的转化方法。为了实现这些目标，我们已经为这段时间的支持建立了具体的目标，以更好地了解FGF-10在刺激尿路上皮细胞周期进展的动态稳态相互关系中的作用。关于FGF-10如何触发增殖的两种机制被假设为：1)FGF-10易位进入尿路上皮细胞核；2)信号级联始于表面受体酪氨酸残基的肝素依赖性磷酸化。我们认为，可忽略不计的FGF-10水平定义了正常的尿路上皮表型-即静止。在增殖期，尿路上皮细胞表面和/或细胞核内的FGF-10水平升高。由于我们制备的重组FGF-10可以诱导动物尿路上皮细胞增殖，我们最终计划评估FGF-10治疗在尿道创伤狭窄疾病和创伤等临床环境中修复尿路上皮的可行性。这项基本作用机制的研究将为以后的临床应用奠定基础。

DESCRIPTION (provided by applicant): 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.