Proteins as Signals in Urothelial Cell Proliferation

描述（由申请人提供）：本竞争性补充的目的是为“蛋白质作为尿路上皮细胞增殖的信号”（1 R01 DK62251; 04/2003 - 02/2008）的范围的显著扩展请求研究支持。请项目负责人于2006年1月1日至2006年3月28日访问英国赫斯灵顿约克大学Jennifer Southgate博士的实验室进行合作实验。这样的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定义参数内触发有丝分裂反应的机制。最初的申请包含一个实验设计，用于在单层细胞培养系统中开发、测试和表征项目的试剂（例如重组蛋白、抗体、培养物和显微镜）。接下来，提到了未来需要发展一种分层的体外培养系统，其中移行上皮将从增殖的，未分化的尿路上皮细胞重建。具体的语言包括访问博士索斯盖特的实验室，以开发这样一个系统。审稿人评论说，这种提议的合作“构成了应用程序的优势”。索斯盖特博士是公认的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著进展，该模型展示了基底、中间和上基底细胞的分层层；细胞角蛋白和表面紧密连接的差异表达；高上皮电阻；对尿素、水和葡聚糖的扩散渗透性低；移行上皮的其他特征。我决定去英国赫斯灵顿的约克大学（University of York），以扩大我资助的R01项目的目标，而不是在西雅图重新发明轮子。预期结果的发表将加强FGF-10 （DK62251）的更新，并显著推进尿路上皮细胞生物学领域。Southgate博士和我在尿路上皮功能障碍（如间质性膀胱炎）方面有共同的研究兴趣，我们的共同工作有望更好地理解尿路上皮细胞、生长因子、基质蛋白、细胞外基质和尿路上皮基底膜之间的稳态相互关系。推进对FGF-10的研究具有重要意义，因为这种多肽有可能作为治疗并最终治愈各种下尿路疾病的临床工具

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