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: 7845024
• 负责人: Indira U Mysorekar
• 金额: $ 24.9万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845024
• 关键词: Ablation; Acute; Address; Adult; Bacteria; Bacterial Infections; Basal Cell; Bladder; Bladder Diseases; Bladder Injury; Bladder Tissue; Carcinogens; Cell Line; Cell Proliferation; Cells; Chemical Agents; Chemical Injury; Chemicals; Chronic; Communicable Diseases; Complex; Disease; Electron Microscopy; Epithelial; Epithelium; Escherichia coli; Escherichia coli Infections; Genes; Gram-Negative Bacteria; Hand; Histology; Human; Immunofluorescence Immunologic; Infection; Inflammation; Inflammatory Response; Injury; Interstitial Cystitis; Light; Malignant neoplasm of urinary bladder; Mediating; Mesenchymal; Mesenchyme; Mitotic Activity; Modality; Modeling; Molecular; Mus; Natural regeneration; Pathway interactions; Patients; Pattern; Phase; Pilot Projects; Process; Protamine Sulfate; Proteins; Regulation; Research; Role; Running; Signal Pathway; Signal Transduction; Site; Stem cells; Stimulus; System; Techniques; Testing; Time; Tissues; Transitional Epithelium; Urinary tract infection; Uropathogenic E. coli; Urothelium; Virulent; Wild Type Mouse; Woman; Work; bladder Carcinoma; bone; bone morphogenetic protein 4; cell injury; cohort; improved; in vivo; injured; interest; loss of function; mouse model; painful bladder syndrome; pathogen; programs; receptor; recombinase; regenerative; repaired; research study; response; response to injury; stem; stem cell niche

The urinary bladder is lined by a transitional urothelium with nonnally slow tumover but substantial injuiyinducible regenerative capacity. Tlie urothelial stem cell (USC) niche, comprising basal stem cells and underlying mesenchyme, fuels the renewal. However, little is known about the molecular features ofthe USCs or the regulatory mechanisms goveming USC niche adaptation in injury or disease. The long term objectives of the research program is to identify the genes, pathways and molecules that govem the rapid, injuryinduced regenerative response of normally quiescent urothelial stem cells (USCs) and to apply what we leam about the nonnal mechanisms to shed light on disease processes with abnormal urothelial tumover (e.g., interstitial cystitis/painful bladder syndrome, bladder cancer). We have developed and study two models of injury, one caused by infection by uropathogenic E. coli (UPEC), the primary causative agent of urinary tract infections (UTIs), and the other by a chemical, protamine sulfate (PS). We show that acute UPEC infection results ui rapid sloughing of superficial cells lining the bladder, marked acute inflammatory response, and a substantial spike in mitotic activity of the USC niche. On the other hand, chemical injury induced by PS causes sloughing but no inflammation and no USC response. We find that epithelial renewal following infectious injury is mediated by the Bone moiphogenetic protein (Bmp) signaling pathway. Inducible cre-recombinase-mediated ablation of the Bmp4 receptor Bmprla in the bladder epithelium resulted in its inability to sustain USC proliferation or regenerate terminally differentiated superficial cells in response to infection. Furthermore, long term infection led to a disruption of epitheUalmesenchymal boundaries and features of qjithelial-to-mesenchymal transition. The specific aims of this application are to elucidate the mechanism tmderlying urothelial response to acute and long term UPEC infection in Bmp4- signaling deficient mice and to elucidate the cellular and molecular underpinnings ofthe urothelial responses to different forms of injury.

膀胱内有移行性尿道上皮，通常移行缓慢，但具有明显的损伤诱导再生能力。由基底干细胞和下层间充质组成的尿路上皮干细胞（USC）龛为更新提供了燃料。然而，对USCs的分子特征以及在损伤或疾病中USCs生态位适应的调控机制知之甚少。该研究计划的长期目标是确定基因，途径和分子，这些基因，途径和分子控制着正常静止的尿路上皮干细胞（USCs）的快速，损伤诱导的再生反应，并应用我们对正常机制的了解来阐明异常尿路上皮细胞的疾病过程（例如，间质性膀胱炎/膀胱疼痛综合征、膀胱癌）。我们已经建立并研究了两种损伤模型，一种是由尿路致病性大肠杆菌感染引起的。大肠杆菌（UPEC），泌尿道感染（UTIs）的主要病原体，另一种是化学物质，硫酸鱼精蛋白（PS）。我们发现，急性UPEC感染导致内衬膀胱的浅表细胞快速脱落，显著的急性炎症反应，以及USC小生境有丝分裂活性的显著增加。另一方面，由PS诱导的化学损伤引起脱落，但没有炎症，也没有USC反应。我们发现感染性损伤后上皮的更新是由骨形态发生蛋白（Bmp）信号通路介导的。诱导性cre重组酶介导的膀胱上皮中Bmp 4受体Bmprla的消融导致其不能维持USC增殖或响应于感染而再生终末分化的浅表细胞。此外，长期感染导致上皮间充质边界的破坏和上皮间充质转化的特征。本申请的具体目的是阐明Bmp 4信号转导缺陷小鼠中尿路上皮对急性和长期UPEC感染的反应机制，并阐明尿路上皮对不同形式损伤的反应的细胞和分子基础。