Transcriptional Regulation of Urothelial Differentiation During Homeostasis and Repair in Response to Urinary Tract Infection

尿路感染的稳态和修复过程中尿路上皮分化的转录调控

• 批准号: 10022310
• 负责人: CATHY Lee MENDELSOHN
• 金额: $ 23.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-24 至 2021-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022310
• 关键词: ATAC-seq; Acute; Adipose tissue; Agonist; Alleles; Apical; Basal Cell; Bladder; Blood; Cell Differentiation process; Cell physiology; Cells; ChIP-seq; Collaborations; Cyclophosphamide; Enterobacteria phage P1 Cre recombinase; Epithelial; Epithelium; Escherichia coli Infections; Event; Exhibits; Exposure to; Family member; Gene Expression Regulation; Genetic; Genetic Transcription; Goals; Homeostasis; Immune; In Vitro; Infection; Injury; Letters; Liver; Mediating; Metabolic; Mission; Modeling; Morphology; Mus; Natural regeneration; Nuclear Receptors; PPAR gamma; Pathway interactions; Pharmaceutical Preparations; Placenta; Poison; Population; Production; Property; Proteins; Research; Role; Squamous Differentiation; Stratum Basale; Stretching; Testing; Toxin; Transcriptional Regulation; Ureter; Urinary tract infection; Urine; Urology; Uropathogenic E. coli; Urothelium; VP 16; Water; Woman; base; cell type; combinatorial; crystallinity; epigenetic regulation; gain of function; genome-wide; in vivo; injured; insulin sensitizing drugs; lipid biosynthesis; loss of function; macrophage; microbial genomics; mouse model; mutant; pathogen; prevent; programs; receptor; regenerative; repaired; response; response to injury; rosiglitazone; selective expression; stem cells; stem-like cell; transcriptome sequencing; urinary

PROJECT 2: PROJECT SUMMARY/ABSTRACT The urothelium is a water-proof epithelium lining ureters and the bladder, that acts as a critical barrier to protect against infection and prevent the exchange of water and toxic substances between the blood and urinary outflow tract. The urothelium is one of the most quiescent epithelia in the body, but can rapidly regenerate in response to injury from exposure to toxins and drugs such as cyclophosphamide or urinary tract infection (UTI), one of the most common infections in women. The urothelium is composed of several sub- populations of cells that may be distinguished based on morphology and expression of combinatorial markers. These sub-populations are crtical to maintaining homeostasis and responding when the urothelium is injured; however, our understanding of the cellular processes that contribute to urothelium homeostatsis and repair in response to injury remain lacking. Our initial results using loss-of-function and gain-of-function mutants, indicate that Peroxisome proliferator-activated receptor gamma (Pparg), a nuclear receptor family member expressed in the urothelium, may be an important regulator of two sub-populations of cells, S-cells and K14- Basal, in vivo. In this application for Project 2 of the Columbia George M. O’Brien Urology Research Center we will use genetic mouse models to identify Pparg-regulated transcriptional pathways that are normally important for urothelial homeostasis, differentiation, and regeneration. Working closely with the Microbial Genomics Biomedical Core, we will characterize cell-type specific functions of Pparg in urothelial homeostasis and regeneration, using a mouse model of Urinary Tract Infection. Additionally, we will determine whether Pparg is important in K14-Basal cells for suppressing squamous differentiation. We will also assess whether activated Pparg can direct K14-Basal cells to undergo an S-cell differentiation program. With these aims, we will fulfill the larger mission of the Columbia O’Brien Center by investigating the genetic and cellular events that are important in maintaining urothelial homeostasis and that contribute to the body’s response to UTI.

项目2：项目总结/摘要 尿道上皮是输尿管和膀胱的防水上皮，其充当重要屏障， 保护免受感染，防止血液和血液之间的水和有毒物质的交换， 泌尿流出道尿路上皮是体内最静止的上皮细胞之一，但可以迅速 对暴露于毒素和药物（如环磷酰胺或尿道）的损伤作出反应而再生 尿路感染（UTI）是女性最常见的感染之一。泌尿系统由几个子系统组成， 可以基于形态学和组合标记物的表达区分的细胞群。 这些亚群对维持内环境稳定和在尿道损伤时做出反应至关重要; 然而，我们对尿道内分泌平衡和修复的细胞过程的理解， 对伤害的反应仍然缺乏。我们使用功能丧失和功能获得突变体的初步结果， 表明核受体家族成员过氧化物酶体增殖物激活受体γ（Pparg 在尿道上皮中表达，可能是两个细胞亚群，S细胞和K14细胞的重要调节因子。 基础，体内。在本申请中，哥伦比亚乔治M。奥布莱恩泌尿外科研究中心， 将使用遗传小鼠模型来识别Pparg调控的转录途径，这些转录途径通常是重要的 用于尿道上皮的稳态、分化和再生。与微生物基因组学密切合作 生物医学核心，我们将描述Pparg在尿路上皮稳态中的细胞类型特异性功能， 再生，使用尿路感染的小鼠模型。此外，我们将确定Pparg是否 在K14基底细胞中重要，用于抑制鳞状分化。我们还将评估是否启动了 Pparg可以指导K14-基底细胞经历S细胞分化程序。有了这些目标，我们将实现 更大的使命的哥伦比亚奥布莱恩中心通过调查遗传和细胞事件， 在维持尿路上皮内环境稳定方面很重要，并有助于机体对UTI的反应。