Mechanisms of epithelial renewal in normal and diseased urinary bladder

正常和患病膀胱的上皮更新机制

• 批准号: 7497149
• 负责人: Indira U Mysorekar
• 金额: $ 8.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2009-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497149
• 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

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.) 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 DSC 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.

作为 NIH 资助的博士后研究员，我独立地制定和测试新的假设 解决重要和常见感染的发病机制中尚未解答的问题，并 总体上提高对泌尿道生物学的理解。实验室内的培训环境， 部门和医学院为解决这些问题提供了宝贵的支持和资源。 结合细胞生物学、遗传学和微生物学的多学科技能，我发现了一些机制 允许大肠杆菌在膀胱上皮内持续存在并重新出现，导致复发 感染。）已经建立了新的、遗传上明确定义的体内模型来描绘复杂和 发育和后续过程中膀胱上皮更新的整合信号网络 我的初步研究结果表明膀胱既具有干细胞依赖性又具有独立性 调节周转的细胞/分子机制，周转的类型可能取决于 损伤，干细胞激活部分受 Bmp4 信号通路调节。功能丧失 Bmp4 通路活性分析将使用诱导性膀胱特异性基因敲除进行 系统确定 DSC 激活响应损伤的作用，并使用组织学进行评估 技术和 qRT-PCR、原位杂交、免疫组织化学分析。小鼠模型来阐明 由一系列诱导的尿路上皮更新的干细胞依赖性和独立机制 将开发刺激并使用细胞识别调节这些过程的分子途径 和全局基因表达分析。该提案的长期目标是确定分子 损伤诱导的尿路上皮祖细胞快速更新的机制和信号通路 细胞并将我们所了解的正常机制应用于异常疾病过程 尿路上皮更新（例如，复发性尿路感染、间质性膀胱炎、膀胱癌）。关联： 该提案将建立系统来研究膀胱干细胞及其在疾病期间如何被激活 例如尿路感染。鉴于倾向，这项工作应该具有巨大的价值和兴趣 膀胱分化在人类疾病中出错，应该有助于改进再生技术 为因疾病而丧失膀胱或受损的患者提供体内或离体膀胱组织。