Program Project: Growth Differentiation and Disease of Urothelium

在过去的11年里，我们作为一个由四个人组成的项目团队工作 具有不同专业知识的研究人员，包括上皮细胞生物学、结构生物学和 在几个密切相关的项目中研究细胞和分子生物学的膜运输 和哺乳动物尿路上皮疾病。我们的研究集中在，作为一个中心和统一的主题， 一组完整的膜蛋白，称为尿板蛋白，代表主要的分化标志物 哺乳动物的尿路上皮。在上一次授权期(2004-2009)，我们的团队展示了 转基因小鼠取消尿路上皮细胞因子导致尿路上皮屏障功能受损 和过度活跃的膀胱；Rab27和Vps33a的缺陷导致梭形小泡和 多囊泡小体的聚集，从而确定它们参与了 Uroplakin转运；FimH可诱导Uroplakin的跨膜构象变化 因此，受体复合体为细菌诱导的宿主细胞变化提供了新的机制； 基因工程小鼠中独特的分子变化构成了这两条途径的基础 尿路上皮肿瘤的发生。因此，我们的团队在探索生物学方面发挥了很好的作用 与尿路上皮生长、分化和疾病有关的重要问题 互动和广泛协作；在有效共享资源方面；在取得 推动尿路上皮生物学领域的重大进展。在接下来的五年资助期内，我们 我将继续作为一个团队工作，提出以下问题：尿路蛋白在 稳定、扩大和修复尿路上皮尖表面(项目1)？他们的角色是什么 包括MAL和Rab27b在内的分子机制在调节尿路蛋白转运中的作用(项目2)？ 尿路蛋白的结构是什么？尿路蛋白复合体是如何锚定在一个潜在的 细胞骨架(项目3)？单独的尿路蛋白及其亚结构域在 Uroplakin受体复合体在介导宿主伞状细胞细菌结合诱导信号中的作用 (项目4)？这种高度协作和协同的团队努力的结果将带来更好的 对尿路上皮功能的了解，并对一些重要的泌尿外科有影响 问题包括膀胱出口梗阻和尿路感染。

Over the past eleven years, we have worked as a Program Project team consisting of four investigators with diverse expertise in the areas of epithelial cell biology, structural biology and membrane trafficking to study, in several closely interrelated projects, the cell and molecular biology and diseases of mammalian urothelium. Our research focuses on, as a central and unifying theme, a group of integral membrane proteins called uroplakins that represent major differentiation markers of mammalian urothelium. During the last granting period (2004-2009), our team has demonstrated that abrogation of uroplakins in transgenic mice resulted in compromised urothelial barrier function and overactive bladder; that defects in Rab27 and Vps33a lead to a depletion of fusiform vesicles and an accumulation of multivesicular bodies, respectively, thus establishing their involvement in uroplakin trafficking; that FimH can induce transmembrane conformational changes in the uroplakin receptor complex thus providing a novel mechanism for the bacterium-induced host cell changes; and that distinctive molecular alterations in genetically engineered mice underlie the two pathways of urothelial tumorigenesis. Our team has therefore functioned well in pursuing biologically important problems related to urothelial growth, differentiation and diseases; in having synergetic interactions and extensive collaborations; in effectively sharing resources; and in having made significant progress advancing the urothelial biology field. During the next five-year grant period, we will continue to work as a team to ask the following questions: What are the roles of uroplakins in the stabilization, enlargement and repair of the urothelial apical surface (Project 1)? What are the roles of molecular machineries including MAL and Rab27b in regulating uroplakin trafficking (Project 2)? What is the structure of uroplakins and how does the uroplakin complex anchor into an underlying cytoskeleton (Project 3)? And what are the roles of individual uroplakins and their subdomains in the uroplakin receptor complex in mediating the bacterial binding-induced signals in host umbrella cells (Project 4)? Results from this highly collaborative and synergetic team effort will lead to a better understanding of urothelial function, and have implications on a number of important urological problems including bladder outlet obstruction and urinary tract infection.