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

总体：项目总结/摘要 哥伦比亚大学乔治M.奥布莱恩泌尿科合作研究中心是由哥伦比亚的 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 良性泌尿外科的核心问题。我们的重点是在前几个周期所开展的工作的基础上，并建议 在临床泌尿学、上皮生物学和微生物学之间的结合点确定临床疾病的解决方案。 我们的教师包括领先的临床和科学头脑在哥伦比亚，包括椅子和教授， 泌尿科、肾脏科、病理学与细胞生物学、遗传学与发育和医学。我们的教师 在三个科学小组中提供专门知识，以确定泌尿系统残疾的根本原因。Gharavi博士 确定了膀胱输尿管反流的主要风险位点，现在正在将发育表型与膀胱输尿管反流和膀胱输尿管反流两者相关联。 尿微生物组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 财团这一努力建立了良性泌尿学的个性化基因组学领域。门德尔松博士 评估Pparg下游的信号传导途径，Pparg是一种核受体，结果证明是一种主要的调节因子， 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，可以作为一个潜在的治疗尿路上皮修复。Barasch博士专注于 在上皮代谢上鉴定了称为“营养免疫”的抵抗UTI的中心机制。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 产生一氧化碳的血红素代谢过程。他的工具包括从少量RNA中分离RNA的新方法 的细胞，新的探针和螯合剂的CO，血红素和铁和报告细菌和小鼠。乌尔曼博士 侧重于耐药微生物的进化基础，破译其分子机制， 毒性。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， 也是微生物组和宏基因组分析的国家资源，也是药物的生物储存库， 耐药UTI分离株。我们团队的兴奋体现在每个组件的相互作用中， 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 周期，我们将继续通过生成新的基因组学数据集（待共享）为泌尿科学做出贡献 dbGAP和GEO）、基因列表、动物模型（保藏在JAX）、细菌基因编辑质粒和试剂 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名新调查员的名册上为新的机会池接受者提供资金 已经获得资助;并继续培训下一代调查人员，在近几年成功的基础上， 90名学生谁受过培训，谁已经出版，获得国家奖项，谁现在是泌尿科医生 和医生。

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.