Retinoic acid signaling controls urothelial development and regeneration.

项目主任/主要研究者（最后，第一，中间）：Mendelsohn，Cathy Lee 项目摘要 尿路上皮是一种上皮屏障，防止水和有毒物质的交换。 血液和尿道之间的物质。它由基底细胞组成， 中间细胞和表面细胞的腔层。表层细胞是 专门用于合成和运输尿斑蛋白，尿斑蛋白是一种蛋白质家族， 进入作为功能性尿路上皮屏障的结晶状顶端斑块。表层细胞 有许多有趣的特征;它们是巨大的，通常是双核的， 是多倍体尿道上皮是人体内最静止的上皮细胞之一， 快速再生，以应对急性损伤，例如泌尿道损伤 感染然而，由于反复接触毒素， 环磷酰胺，可导致屏障妥协，炎症和疾病，如 膀胱疼痛综合征，一种改变生命的疾病，目前还没有治愈的方法。 这些拟议的研究建立在我们实验室以前的发现基础上， 尿路上皮祖细胞对发育和再生很重要。在 在本申请中，我们将使用谱系分析和器官培养以及活的 成像以显现成年野生型和突变型尿路上皮祖细胞的行为。 我们将进行初步研究，表明基底细胞，这是单能的， 在急性损伤期间，获得产生中间和表面细胞的潜力 慢性损伤后的孩子我们鉴定了Pparg，一种核受体，以其 在脂肪形成中的作用，作为维甲酸的潜在靶点，我们表明Pparg是 对浅表细胞的形成和再生至关重要，也调节基底细胞 体内平衡，防止鳞状分化。除了它在人类生活中的重要作用外， 健康，泌尿系统也是引起不同类型膀胱的细胞来源 癌的尿路上皮祖细胞的鉴定及其调控的信号通路 它们对于开发再生和修复的治疗策略将是重要的， 以及了解尿路上皮分化是如何出错的。

Program Director/Principal Investigator (Last, First, Middle): Mendelsohn, Cathy Lee Project Summary The urothelium is an epithelial barrier that prevents exchange of water and toxic substances between the blood and urinary tract. It is composed of basal cells, Intermediate cells and a luminal layer of superficial cells. Superficial cells are specialized for synthesis and transport of uroplakins, a family of proteins that assemble into the crystalline apical plaque that is the functional urothelial barrier. Superficial cells have a number of interesting features; they are enormous, generally binucleated and are polyploid. The urothelium is one of the most quiescent epithelia in the body, but quickly regenerates in response to acute damage, for example from urinary tract infection. Chronic injury however, from repeated exposure to toxins such as cyclophosphamide, can lead to barrier compromise, inflammation and disease such as bladder pain syndrome, a life altering condition for which there is no cure at present. These proposed studies build on previous findings from our lab that identify novel urothelial progenitors that are important for development and regeneration. In the present application, we will use lineage analysis and an organ culture together with live imaging to visualize the behavior of adult wild type and mutant urothelial progenitors. We will pursue preliminary studies suggesting that Basal cells, which are unipotent during acute injury, acquire the potential to produce Intermediate and Superficial cell daughters after chronic injury. We identify Pparg, a nuclear receptor best known for its role in adipogenesis, as a potential target of Retinoids, and we show that Pparg is critical for formation and regeneration of Superficial cells, and also regulates basal cell homeostasis, preventing squamous differentiation. Besides its critical role in human health, the urothelium is a also source of cells that give rise to different types of bladder cancers. Identification of urothelial progenitors and the signaling pathways that control them will be important for developing therapeutic strategies for regeneration and repair, and for understanding how urothelial differentiation can go wrong.