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Mechanisms of epithelial renewal in normal and diseased urinary bladder

正常和患病膀胱的上皮更新机制

基本信息

批准号：
7385337
负责人：
Indira U Mysorekar
金额：
$ 8.3万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-20 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7385337
关键词：
Acute Address Adult Bacteria Bacterial Infections Basal Cell Biology Bladder Bladder Injury Bladder Tissue Carcinogens Cell Proliferation Cells Cellular biology Chemical Agents Chemical Injury Chronic Communicable Diseases Complex Development Disease Electron Microscopy Environment Epithelial Epithelium Escherichia coli Escherichia coli Infections Funding Gene Expression Genetic Goals Gram-Negative Bacteria Histological Techniques Histology Human Immunofluorescence Immunologic In Situ Hybridization Infection Inflammation Inflammatory Response Injury Interstitial Cystitis Learning Localized Malignant neoplasm of urinary bladder Mediating Microbiology Mitotic Activity Modality Molecular Mus Natural regeneration Pathogenesis Pathway interactions Patients Pattern Phase Pilot Projects Postdoctoral Fellow Process Protamine Sulfate Proteins Rate Recurrence Regulation Resources Role Running Signal Pathway Signal Transduction Site Stem cells Stimulus System Techniques Testing Time Tissues Training Transitional Epithelium Urinary tract Urinary tract infection Uropathogenic E. coli Urothelium Virulent Wild Type Mouse Woman Work bladder Carcinoma bone morphogenetic protein 4 cell injury cohort day human disease improved in vivo in vivo Model injured interest knockout gene loss of function medical schools mouse model pathogen repaired research study response response to injury skills stem

项目摘要

DESCRIPTION (provided by applicant): As an NIH-funded post-doctoral fellow, I have worked independently to formulate and test new hypotheses to address unanswered questions in the pathogenesis of an important and common infection, and to improve the understanding of urinary tract biology, in general. The training environment within the lab, department, and medical school provide invaluable support and resources to pursue these questions. Blending multi-disciplinary skills in cell biology, genetics, and microbiology, I discovered mechanisms that permit persistence of E. coli within the bladder epithelium and enable re-emergence to cause recurrent infections. I have established new and genetically well-defined in vivo models to delineate the intricate and integrated signaling network underlying bladder epithelial renewal during development and following injury. My preliminary findings suggest that the bladder has both stem cell-dependent and independent cellular/molecular mechanisms to regulate turnover, that the type of turnover may depend on the type of injury, and that stem cell activation is in part regulated by the Bmp4 signaling pathway. Loss of function analysis of Bmp4 pathway activity will be performed using an inducible bladder-specific gene knockout system to determine a role in USC activation in response to injury and evaluated using histological techniques and qRT-PCR, in situ hybridization, immunohistochemical analyses. Mouse models to elucidate the stem-cell dependent and independent mechanisms of urothelial renewal induced by a spectrum of stimuli will be developed and molecular pathways regulating these processes will be identified using cellular and global gene expression analyses. The longterm goal of this proposal is to identify the molecular mechanisms and signaling pathways underlying the rapid, injury-induced renewal of urothelial progenitor cells and to apply what we learn about the normal mechanisms to disease processes with abnormal urothelial turnover (e.g., recurrent urinary tract infections, interstitial cystitis, bladder cancer). Relevance: This proposal will establish systems to study bladder stem cells and how they are activated during diseases such as urinary tract infections. This work should be of tremendous value and interest, given the propensity for bladder differentiation to go awry in human diseases and should help improve techniques to regenerate bladder tissue in vivo or ex vivo for patients whose bladders have been lost or damaged due to disease.

描述（由申请人提供）：