Program Project: Growth Differentiation and Disease of Urothelium

计划项目：尿路上皮的生长分化和疾病

• 批准号: 8694872
• 负责人: Tung-Tien Sun
• 金额: $ 145.68万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8694872
• 关键词: Apical; Area; Bacteria; Binding; Biochemistry; Biology; Bladder; Bladder Neoplasm; Bladder Urothelium; Cell Cycle Deregulation; Cells; Cellular biology; Collaborations; Complex; Cytoskeleton; Data; Defect; Differentiation Antigens; Differentiation and Growth; Disease; Epithelial Cells; Event; Functional disorder; Genes; Genetically Engineered Mouse; Grant; Individual; Infection; Integral Membrane Protein; Knock-out; Knockout Mice; Lead; Lectin; Mechanics; Mediating; Membrane; Membrane Protein Traffic; Membrane Proteins; Microfilaments; Modeling; Molecular; Molecular Biology; Multivesicular Body; Obstruction; Overactive Bladder; Papillary; Papillary Neoplasm; Pathway interactions; Permeability; Play; Program Research Project Grants; Proteins; Receptor Protein-Tyrosine Kinases; Recurrence; Recycling; Research; Research Personnel; Resource Sharing; Role; Signal Transduction; Sorting - Cell Movement; Stretching; Structure; Surface; System; The Sun; Time; Transgenic Mice; Transmembrane Domain; Tumor Biology; Tumor Suppressor Proteins; UPK2 gene; Urinary tract infection; Uropathogenic E. coli; Urothelium; Vesicle; Work; apical membrane; in vivo; nexin; novel; particle; programs; receptor; repaired; response; structural biology; trafficking; tumorigenesis; urologic

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.

在过去的11年里，我们作为一个由4人组成的项目团队工作