Investigating the Genetic, Cellular, and Metabolic Events Important for Urothelial Homeostasis and Response to Injury

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由哥伦比亚大学的 领先的泌尿科医生、微生物学家、遗传学家、发育和细胞生物学家致力于解决 良性泌尿系统的中心问题。我们的重点是建立在前几个周期进行的工作基础上，并建议 在临床泌尿学、上皮生物学和微生物学的交界处确定临床疾病的解决方案。 我们的教职员工包括哥伦比亚大学领先的临床和科学头脑，包括 泌尿学、肾脏病、病理学和细胞生物学、遗传学与发育和医学。我们的教职员工一起 提供专业知识，在三个科学小组中确定泌尿系残疾的根本原因。Gharavi博士已经 确定了膀胱输尿管返流的主要危险基因，现在正在将发育表型与两者相关联 尿菌群和下尿路症状的变化。Gharavi博士的工具包括大型数据集 如下尿路症状研究网络(Lurn)、英国生物库和Emerge 财团。这一努力奠定了良性泌尿外科个性化基因组学领域的基础。门德尔松博士 评估PPARG下游的信号通路，PPARG是一种核受体，被证明是 尿路上皮细胞类型特异性分化，以及对损伤和感染的炎症反应。 这项工作确定了一种现成的药物，可以作为尿路上皮修复的潜在治疗方法。巴拉施博士关注的是 关于上皮新陈代谢的研究确定了一种防御尿路感染的中心机制，称为“营养免疫”。他 发现NGAL是一种阻止细菌捕获铁的蛋白质，现在已经确定了一种高度活跃的途径 产生一氧化碳气体的血红素代谢。他的工具包括从少量RNA中提取RNA的新方法 细胞、一氧化碳、血红素和铁的新型探针和螯合剂，以及报告细菌和小鼠。乌尔曼博士 重点阐述了耐药微生物的进化基础，破译了它们的分子机制 致命性。微生物基因组学生物医学核心不仅指导奥布莱恩的所有微生物学研究，而且 也是微生物组和元基因组分析的国家资源，以及药物的生物储存库- 耐药UTI分离株。我们团队的兴奋被封装在每个组件的互动中 从基因发现到治疗应用的研究，包括人类和小鼠模型。在这个新的 周期，我们将继续通过生成新的基因组数据集(将被共享)来为泌尿科学做出贡献 在DBGaP和GEO上)、基因列表、动物模型(保存在JAX)、细菌基因编辑质粒和试剂 这可以与泌尿科社区分享。我们将继续与威斯康星州的泌尿科专家合作， 密苏里州，马里兰州。我们将在6名新调查人员的基础上，为新的机会池获奖者提供资金 已经获得资金；并在近几年成功的基础上继续培训下一代调查人员 90名接受过培训并发表过论文的学生获得了国家奖项，他们现在是泌尿科医生 还有医生。

OVERALL: PROJECT SUMMARY/ABSTRACT The Columbia University George M. O’Brien Urology Cooperative Research Center is made up of Columbia’s leading Urologists, Microbiologists, Geneticists, Developmental and Cell Biologists dedicated to solving the central problems of Benign Urology. Our focus builds on the work conducted in prior cycles and proposes to identify solutions to clinical diseases at the juncture between clinical urology, epithelial biology and microbiology. Our faculty include the leading clinical and scientific minds at Columbia, including Chairs and Professors of Urology, Nephrology, Pathology & Cell Biology, Genetics & Development and Medicine. Together our faculty provide the expertise to identify the root causes of urologic disability in three scientific groups. Dr Gharavi has identified major risk loci for vesiculoureteral reflux and is now correlating developmental phenotypes with both changes in the urinary microbiome and lower urinary tract symptoms. Dr Gharavi’s tools include large datasets such as the Lower Urinary Tract Symptoms Research Network (LURN), the UK Biobank and the eMERGE consortium. This effort establishes the field of personalized genomics in benign urology. Dr Mendelsohn evaluates signaling pathways downstream of Pparg, a nuclear receptor that turns out to be a major regulator of cell type specific differentiation in the urothelium, as well as the inflammatory response to injury and infection. The work identifies an off-the-shelf drug that can be a potential treatment for urothelial repair. Dr Barasch focuses on epithelial metabolism identifying a central mechanism of defense against UTI called “nutritional immunity”. He discovered NGAL a protein that blocks iron capture by bacteria, and now has identified a highly active pathway of heme metabolism that produce CO gas. His tools include novel methods of RNA isolation from small amounts of cells, novel probes and chelators of CO, of heme and iron and reporter bacteria and mice. Dr Uhlemann focuses on the evolutionary basis of drug-resistant microorganisms deciphering their molecular mechanisms of virulence. The Microbial Genomics Biomedical Core not only directs all microbiological studies in the O’Brien but also serves as a national resource for microbiome and metagenomic analyses and as a biorepository for drug- resistant UTI isolates. The excitement of our group is encapsulated in the interactions of each component of research from gene discovery to therapeutic applications including both human and mouse models. In this new cycle, we will continue to contribute to urological sciences by generating new genomics datasets (to be shared on dbGAP and GEO), gene lists, animal models (deposited at JAX), bacterial gene editing plasmids and reagents that can be shared with the urology community. We will continue to collaborate with urology experts in Wisconsin, Missouri, Maryland. We will fund new Opportunity Pool recipients, building on the roster of 6 new investigators already funded; and continue to train the next generation of investigators, building on the success of the nearly 90 students who have trained and who have published, received national awards and who are now Urologists and medical doctors.