Molecular models of urothelial renewal and cancer

描述（由申请人提供）：本提案旨在通过一种具有良好特征的尿路感染（uti）小鼠模型，描述膀胱上皮更新和癌变的分子机制和信号通路。在这个模型中，宿主对尿路致病性大肠杆菌（UPEC）感染的防御反应导致尿路上皮更新过程的快速但受控的激活。正常尿路上皮更新的关键分子调控因子包括Bmp4和Shh信号通路，它们也可能在膀胱癌的发展过程中发生突变或消失。将对这些通路进行功能丧失分析，以确定它们在膀胱癌发生中的作用。此外，将比较野生型和Shh-或bmp4信号缺陷小鼠膀胱中尿路上皮对UPEC感染和BCG免疫治疗（膀胱癌的主要治疗方法）的反应。了解这些途径在膀胱癌发生中的作用可能会导致使用UPEC作为靶向递送系统治疗膀胱癌的治疗方式的发展。最后，将开发体外尿路上皮外植体模型来测试Shh-或bmp4信号通路的药理调节。

DESCRIPTION (provided by applicant): This proposal aims to delineate the molecular mechanisms and signaling pathways underlying epithelial renewal and carcinogenesis in the bladder using a well-characterized mouse model of urinary tract infections (UTIs). In this model, the host defense response to infection with uropathogenic E. coli (UPEC) results in a rapid but controlled activation of the urothelial renewal process. Key molecular regulators of normal urothelial renewal include the Bmp4 and Shh signaling pathways, which may also be mutated or abrogated during development of bladder carcinoma. Loss of function analyses of these pathways will be performed to determine their role in bladder carcinogenesis. In addition, the urothelial responses to UPEC infection and BCG immunotherapy (a major treatment for bladder carcinoma) will be compared and contrasted in wild type, and Shh- or Bmp4-signaling deficient mouse bladders. Understanding the role of these pathways in bladder carcinogenesis may lead to development of therapeutic modalities for bladder carcinoma treatment using UPEC as a targeted delivery system. Finally, in vitro urothelial explant models will be developed to test pharmacological modulation of the Shh- or Bmp4-signaling pathways.