The Genetic Origins and Complications of Urinary Tract Abnormalities

总体描述(由申请者提供)：哥伦比亚大学乔治·M·奥布莱恩泌尿学合作研究中心汇集了一批经验丰富的研究人员，他们有着长期富有成效的合作记录，以解决良性泌尿外科的一个主要问题。膀胱输尿管反流、后尿道瓣和相关形式的尿路 梗阻是人类常见的先天缺陷，占儿童慢性肾功能衰竭的20%。肾脏损害可能是由于固有的遗传异常，损害了肾脏形成和输尿管功能，或者可能与反复发热性尿路感染相关的疤痕形成有关。该中心将采用多学科方法来解决人类和小鼠模型中发育缺陷及其并发症的起源。该中心由3个研究项目、2个试点项目和一个行政核心组成。项目1将采用一种全面的基因组学方法来阐明人类VUR的发病机制，方法是研究Gwas、CNV分析和外显子组测序方法可以发现的常见和罕见变异之间的相互作用。项目2将利用缺乏SALL1和RA信号的小鼠突变体研究泌尿生殖窦在后尿道瓣和梗阻发生中的作用，这两种信号都显示出梗阻。项目3将研究结构缺陷和阿尔法嵌入细胞分泌的抗微生物蛋白在尿路感染和肾脏损伤发展过程中的相互作用。这些项目 与之相辅相成的是创新的试点建议，旨在通过人类队列后尿道瓣(试点1)的外显子组测序发现罕见的突变，并通过对近亲交配的小鼠品系进行GWA来定位易受尿路感染的基因座。(试播2)。每个这些项目的科学目标都是高度相互关联的，需要积极交流思想、无缝共享数据以及多学科协作努力才能取得成功。因此，这个项目的一个中心主题是作为泌尿外科研究人员之间合作活动和数据共享的典范，通过这些项目，我们将开发在泌尿外科社区内传播科学发现的模式。最后，我们的奥布莱恩中心主要强调对下一代临床医生和泌尿外科研究科学家的教育，包括年度研讨会、双月系列研讨会、暑期学生培训计划和少数族裔外展计划。我们还将使用机会池机制与NIDDK P20规划中心和K12 Kure中心互动，以吸引新的研究人员研究良性泌尿外科的重要问题。

DESCRIPTION, OVERALL (provided by applicant): 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 a major problem in benign urology. Vesicoureteral reflux, posterior urethral valves and related forms of urinary tract obstruction are common birth defects in humans and account for 20% chronic kidney failure in children. Kidney damage can be due to intrinsic genetic abnormalities that impair both nephrogenesis and ureteric function, or may be linked to scarring associated with recurrent febrile UTIs. This Center will employ a multidisciplinary approach to address the origins of development defects and their complications in humans and mouse models. The Center consists of 3 research projects, 2 pilot projects and an administrative core. Project 1 will undertake a comprehensive genomics approach to elucidate the pathogenesis of VUR in humans by examining the interplay between common and rare variants that can be discovered by GWAS, CNV analysis and exome sequencing approaches. Project 2 will study the role of the urogenital sinus in the genesis of posterior urethral valves and obstruction using mouse mutants lacking Sall1 and RA-signaling, both of which display obstruction. Project 3 will examine the interaction between structural defects and antimicrobial proteins secreted by the alpha-intercalated cells in the development of urinary tract infections and kidney injury. These projects are complemented by innovative pilot proposals that aim to discover rare mutations by exome sequencing in human cohorts posterior urethral valves (Pilot 1) and map loci predisposing to urinary tract infection by performing a GWAS in inbred mouse strains. (Pilot 2). The scientific aims of each these projects are highly interconnected, and will require vigorous exchange of ideas, seamless data sharing and multidisciplinary, collaborative efforts to achieve success. Thus, a central theme of this project is to serve as a model for collaborative activity and data sharing between urology investigators and through these projects, we will develop models for dissemination of scientific findings within the urology community. Finally, our O'Brien center has a major emphasis on education of the next generation of clinician-scientists in Urologic research, with annual workshops, bimonthly seminar series, summer student training programs, and minority outreach programs. We will also use the opportunity pool mechanism to interact with the NIDDK P20 planning centers and K12 KURe centers to attract new investigators to study important problems in benign urology.