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

项目2：项目摘要/摘要 尿路上皮是一种防水的上皮，覆盖在输尿管和膀胱内，起着关键的屏障作用。 防止感染，防止水和有毒物质在血液和血液之间的交换 尿流出道。尿路上皮是体内最静止的上皮之一，但可以迅速 因接触毒素和药物(如环磷酰胺或尿路)而再生 感染(UTI)，女性最常见的感染之一。尿路上皮由几个亚细胞组成。 可根据组合标记的形态和表达来区分的细胞群体。 这些亚群对维持尿路上皮损伤时的动态平衡和反应至关重要； 然而，我们对尿路上皮细胞平衡和修复的细胞过程的理解 对受伤的反应仍然缺乏。我们使用功能丧失和功能获得突变体的初步结果， 提示核受体家族成员PPARG是一种核受体家族成员 在尿路上皮细胞中表达，可能是S细胞和K14细胞两个亚群的重要调节因子。 基本的，活体的。在这份哥伦比亚大学乔治·M·奥布莱恩泌尿外科研究中心项目2的申请表中，我们 将使用遗传小鼠模型来识别PPARG调节的转录途径，这些途径通常是重要的 用于尿路上皮的动态平衡、分化和再生。与微生物基因组学密切合作 生物医学核心，我们将表征PPARG在尿路上皮动态平衡和细胞类型中的特定功能 再生，采用小鼠尿路感染模型。此外，我们将确定PPARG是否为 在抑制鳞状细胞分化的K14-Basal细胞中很重要。我们还将评估是否已激活 PPARG可以引导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 哥伦比亚奥布莱恩中心的更大使命是通过研究 对维持尿路上皮动态平衡很重要，有助于人体对尿路感染的反应。

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.