Investigating the Genetic, Cellular, and Metabolic Events Important for Urothelial Homeostasis and Response to Urinary Tract Infection

总体：项目摘要/摘要 哥伦比亚大学乔治·M·奥布莱恩泌尿外科合作研究中心汇集了 一组经验丰富的调查人员，具有长期的卓有成效的合作记录，以解决 最常见的良性泌尿生殖系统疾病是尿路感染(UTI)。尿路感染在美国很普遍 有13.3%的女性、2.3%的男性和3.4%的儿童因大肠杆菌而需要医疗干预 尿路、膀胱、输尿管和肾的感染。自2014年以来，哥伦比亚·奥布莱恩研究中心 调查了导致儿童泌尿生殖系统常见发育缺陷的原因。 人和小鼠模型中的尿路梗阻。对于提议的续签申请，中心将建立 在这些努力的基础上，采用多学科的方法来解决遗传、细胞和代谢事件 它们对维持尿路上皮内环境平衡很重要，有助于人体对尿路感染的反应。这个 该中心由三个研究项目组成，一个新的微生物基因组学生物医学核心(MGBC)和一个 管理核心。项目1将确定宿主基因组和尿液微生物组对 尿路感染，以及人类的泌尿生殖系统结构缺陷。项目2将使用鼠标模型来研究如何 尿路上皮细胞分化的转录调控在正常动态期和修复期不同 UTI。项目3将阐明一种新的代谢途径--“血红素机器”--如何调节膀胱内的尿路感染。 每个项目的科学目标都是高度相互关联的，需要动态地交换 知识、无缝数据共享以及多学科、协作的努力才能取得成功。要实现 为了实现这些目标，这三个项目将得到MGBC的支持，MGBC将为 生物库，扩展细菌培养，微生物基因组学(微生物组分析，比较基因组学， RNAseq)、微生物遗传学和研究设计咨询。此外，行政核心将提供 项目和MGBC的支持框架除了整合和监督中心的 活动包括教育充实计划和机会池计划。在过去五年中 多年来，该中心一直将重点放在培养下一代临床医生--泌尿外科科学家上 研究，包括年度静修、研讨会系列、暑期学生培训计划和少数族裔外展 程序。我们还成功地使用机会池机制与NIDDK资助的其他 中心，并吸引新的研究人员来研究良性泌尿外科的重要疾病。建立在我们的 过去五年的经验，并利用哥伦比亚大学一流生物医学研究的基础设施 机构，这项拟议的更新将继续促进基础、 翻译和临床研究人员。该中心还将解决与遗传、细胞和 导致尿路感染的代谢事件，同时提供教育丰富和参与的机会 来自泌尿外科和其他领域的研究人员服务于更大的泌尿外科研究社区。

OVERALL: PROJECT SUMMARY/ABSTRACT The Columbia University George M. O’Brien Urology Cooperative Research Center brings together an experienced group of investigators with a long track record of productive collaboration to address the causes of the most common benign genitourinary disease, urinary tract infection (UTI). UTIs are prevalent in the United States with 13.3% of women, 2.3% of men and 3.4% of children requiring medical intervention due to E. coli infection of the urethra, bladder, ureter, and kidney. Since 2014, the Columbia O’Brien Research Center has investigated the origins of common developmental defects of the pediatric genitourinary system that cause urinary tract obstruction in human and mouse models. For the proposed renewal application, the Center will build upon these efforts and employ a multidisciplinary approach to address the genetic, cellular, and metabolic events that are important in maintaining urothelial homeostasis and that contribute to the body’s response to UTI. The Center consists of three Research Projects, a new Microbial Genomics Biomedical Core (MGBC), and an Administrative Core. Project 1 will determine the influence of the host genome and the urinary microbiome in UTI, as well as genitourinary structural defects in humans. Project 2 will use mouse models to investigate how the transcriptional regulation of urothelial differentiation differs between normal homeostasis and repair during UTI. Project 3 will elucidate how a novel metabolic pathway, the “heme machine”, regulates UTI in the bladder. The scientific aims for each of these projects are highly interconnected, and will require a dynamic exchange of knowledge, seamless data sharing, and multidisciplinary, collaborative efforts to achieve success. To achieve these aims, the three projects will be supported by the MGBC that will provide high-quality services for biobanking, extended bacterial culture, microbial genomics (microbiome analyses, comparative genomics, RNASeq), microbial genetics, and consultation for study design. Additionally, the Administrative Core will provide the supporting framework for the Projects and MGBC in addition to integrating and overseeing all of the Center’s activities including the Educational Enrichment Program and the Opportunity Pool Program. Over the past five years, the Center has placed a major emphasis on educating the next generation of clinician-scientists in urologic research, with annual retreats, seminar series, a summer student training program, and minority outreach programs. We have also successfully used the Opportunity Pool mechanism to interact with other NIDDK-funded centers and to attract new investigators to study important disorders in benign urology. Building on our experience from the last five years and leveraging the infrastructure of Columbia’s top-tier biomedical research institution, this proposed renewal will continue to foster multi- and interdisciplinary collaborations between basic, translational, and clinical researchers. The Center will also address questions related to the genetic, cellular, and metabolic events that lead to UTI, while providing opportunities for educational enrichment and engaging investigators from within urology and other fields to serve the larger urological research community.