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: 6619966
• 负责人: JAMES A BASSUK
• 金额: $ 25.79万
• 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/6619966
• 关键词: biological signal transduction; biopsy; cell differentiation; cell growth regulation; cell proliferation; child (0-11); clinical research; confocal scanning microscopy; cytokine; fibroblast growth factor; gene expression; growth factor receptors; human tissue; in situ hybridization; phosphorylation; protein structure function; receptor; southern blotting; tissue /cell culture; urinary bladder epithelium; western blottings

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.

描述（由申请人提供）：了解尿路上皮的生长和区分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。我们实验室中的初步证据表明，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，这是涉及对尿皮皮细胞生长，分化和修复的关键过程。该过程由起源于间质的复杂的旁分泌作用网络描述，但作用于尿皮上皮。 FGF10-NULL小鼠中这种过程的破坏改变了膀胱尿路上皮细胞的分化，并导致异常的过渡上皮，构成了不完全分层。控制尿路上皮的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的FGF-10部分，因为a）a）对膀胱中FGF-10的生物学一无所知，b）了解FGF-10如何与其他这些过程结合起来，使我们能够开发出新的和创新的方法来增强我们对Bladder and Irilary Tract疾病的方法来加强我们的方法。为了实现这些目标，我们已经为这段时期建立了特定的目标，以更好地了解FGF-10在动态稳态相互关系的背景下如何刺激尿路上皮细胞周期的进展。假设FGF-10如何触发增殖的两种机制：1）FGF-10的易位到尿路上皮细胞核中，以及2）一个信号级联，这是从肝素依赖的表面受体残基的磷酸依赖性磷酸化开始的。我们认为，FGF -10水平可忽略不计，定义了静止的正常尿路上皮表型。在增殖阶段，尿路上皮细胞表面和/或尿路上皮细胞核内FGF-10的水平上升。由于我们的重组FGF-10的制剂会诱导动物的尿路上皮细胞增殖，因此我们最终计划评估FGF-10疗法在修复临床环境（例如尿道创伤狭窄疾病和创伤等临床环境）中的尿路上皮方面的尿。这项对作用基本机制的研究将为以后的临床使用奠定了基础。