PROTEINS AS SIGNALS IN UROTHELIAL CELL PROLIFERATION

蛋白质作为尿路上皮细胞增殖的信号

• 批准号: 6833972
• 负责人: JAMES A BASSUK
• 金额: $ 26.02万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6833972
• 关键词: PROTEINS; SIGNALS; UROTHELIAL; CELL; PROLIFERATION

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================

超出提供的空间。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进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-10在调节尿路上皮细胞DNA合成方面发挥重要作用，而DNA合成是控制尿路上皮细胞生长、分化和修复的关键过程。这一过程由一个复杂的旁分泌作用网络描述，该网络起源于间充质，但作用于尿路上皮。在FGF10基因缺失的小鼠中，这一过程的中断改变了膀胱尿路上皮细胞的分化，并导致了以不完全复层为典型的异常过渡上皮。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成纤维细胞生长因子-10部分，因为a)对成纤维细胞生长因子-10在膀胱中的生物学一无所知，以及b)了解成纤维细胞生长因子-10如何与这些其他过程一起工作，将使我们能够开发新的创新方法来加强我们对膀胱和尿路疾病问题的翻译方法。为了实现这些目标，我们为这一时期的支持制定了具体的目标，以更好地了解成纤维细胞生长因子-10如何在刺激尿路上皮细胞周期进展的动态稳态相互关系中发挥作用。有两种机制可以解释成纤维细胞生长因子10是如何触发细胞增殖的：1)成纤维细胞生长因子10移位到尿路上皮细胞核中；2)以肝素依赖的表面受体酪氨酸残基的磷酸化开始的信号级联反应。我们认为，可以忽略不计的成纤维细胞生长因子-10水平定义了正常的尿路上皮细胞表型--静止型。在增殖期，尿路上皮细胞表面和/或细胞核内的成纤维细胞生长因子-10水平升高。由于我们制备的重组成纤维细胞生长因子-10可诱导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治疗在临床环境中修复尿路上皮的可行性，如尿路创伤、狭窄疾病和创伤。这一基本作用机制的研究将为以后的临床应用奠定基础。表演网站========================================Section End===========================================