Proteins as Signals in Urothelial Cell Proliferation

描述（由申请人提供）：本竞争性补充文件的目的是请求研究支持，以显著扩大“蛋白质作为尿路上皮细胞增殖的信号”（1 R 01 DK 62251; 04/2003 - 02/2008）的范围。为了进行合作实验，要求PI在2006年1月1日至2006年3月28日期间访问英国赫斯灵顿约克大学的Jennifer索斯盖特博士的实验室。这种实验旨在更好地理解成纤维细胞生长因子-10在体外尿路上皮细胞培养模型的限定参数内触发促有丝分裂应答的机制。原始申请包含在单层细胞培养系统中开发、检测和表征项目试剂（例如重组蛋白、抗体、培养物和显微镜检查）的实验设计。接下来，提到了未来需要开发一种分层的体外培养系统，其中移行上皮将由增殖的、未分化的尿路上皮细胞重建。具体的语言包括访问索斯盖特博士的实验室，以开发这样一个系统。审查人员评论说，这一拟议的合作“构成了申请的一个优势”。索斯盖特博士被公认为尿路上皮细胞生物学的世界领导者。她的实验室在开发仿生三维尿路上皮培养模型方面取得了显着进展，该模型具有基底层，中间层和基底上层细胞的分层;细胞角蛋白和表面紧密连接的差异表达;高跨上皮电阻;对尿素，水和葡聚糖的低扩散渗透性;以及天然移行上皮的其他特征。我没有在西雅图重新发明轮子，而是决定前往英国赫斯灵顿的约克大学，扩大我资助的R 01的目标。预计由此产生的出版物将加强FGF-10（DK 62251）的更新，并显着推进尿路上皮细胞生物学领域。索斯盖特博士和我在尿路上皮功能障碍（例如间质性膀胱炎）方面有着共同的研究兴趣，我们的联合工作有望更好地理解涉及尿路上皮细胞、生长因子、基质细胞蛋白、细胞外基质和尿路上皮基底膜的稳态相互关系。推进FGF-10的研究是相关的，因为该多肽作为治疗并最终治愈各种下尿路病症和疾病的临床工具的潜在用途

DESCRIPTION (provided by applicant): The purpose of this competing supplement is to request research support for significant expansion of the scope of "Proteins as Signals in Urothelial Cell Proliferation" (1 R01 DK62251; 04/2003 - 02/2008). Support is requested for the PI to visit the laboratory of Dr. Jennifer Southgate at the University of York, Heslington, United Kingdom, from 01/01/2006 - 03/28/2006, for the purpose of collaborative experimentation. Such experimentation is designed to better understand the mechanisms by which Fibroblast Growth Factor-10 triggers a mitogenic response within defined parameters of in vitro urothelial cell culture models. The original application contained an experimental design to develop, test, and characterize the project's reagents (e.g. recombinant proteins, antibodies, cultures, and microscopy) in a monolayer cell culture system. Next, mention was made for a future need to develop a stratified in vitro culture system where transitional epithelium would be reconstituted from proliferative, non-differentiated urothelial cells. Specific language was included to visit Dr. Southgate's laboratory in order to develop such a system. The Reviewers commented that this proposed collaboration "constituted a strength of the application". Dr. Southgate is recognized as a world leader in urothelial cell biology. Her laboratory has made remarkable progress in developing a biomimetic 3-dimensional urothelial culture model that exhibits stratified layers of basal, intermediate, and suprabasal cells; differential expression of cytokeratins and superficial tight junctions; high transepithelial electrical resistance; low diffusive permeability to urea, water, and dextran; and other characteristics of native transitional epithelium. Instead of reinventing the wheel in Seattle, a decision has been made to travel to the University of York, Heslington, UK, to expand the Aims of my funded R01. It is expected that resultant publications will strengthen the renewal of the FGF-10 (DK62251) and significantly advance the field of urothelial cell biology. Dr. Southgate and I share funded interests in urothelial dysfunction, e.g. interstitial cystitis, and our joint work is expected to lead to a better understanding of the steady-state interrelationships that involve urothelial cells, growth factors, matricellular proteins, the extracellular matrix, and the urothelial basement membrane. Advancing the study of FGF-10 is relevant because of the polypeptide's potential use as a clinical tool to treat, and ultimately cure, a variety of lower urinary tract conditions and diseases