PROTEINS AS SIGNALS IN UROTHELIAL CELL PROLIFERATION

描述（由申请人提供）：了解尿路上皮细胞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，这是一个参与控制尿路上皮生长、分化和修复的关键过程。这一过程是由一个复杂的网络旁分泌行动，起源于间充质，但对尿路上皮的行为。FGF 10基因敲除小鼠中这一过程的中断改变了膀胱尿路上皮细胞的分化，并导致以不完全分层为代表的异常移行上皮。参与控制尿路上皮生长和分化的其他过程包括各种类型的细胞因子和生长因子。 我们建议攻击这些过程中的FGF-10部分，因为a）对FGF-10在膀胱中的生物学一无所知，以及B）了解FGF-10如何与这些其他过程一起工作将使我们能够开发新的和创新的方法来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，我们已经为这一时期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功能。假设了FGF-10触发增殖的两种机制：1）FGF-10移位到尿路上皮细胞核中; 2）始于表面受体酪氨酸残基的肝素依赖性磷酸化的信号级联反应。我们认为，FGF-10的水平可以忽略不计定义正常的尿路上皮表型-静止。在增殖阶段，FGF-10的水平在尿路上皮细胞表面和/或尿路上皮细胞核内升高。由于我们的重组FGF-10制剂在动物中诱导尿路上皮细胞增殖，我们最终计划评估FGF-10治疗在修复尿道损伤、尿道狭窄疾病和创伤等临床环境中的可行性。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.