The Genetic Origins and Complications of Urinary Tract Abnormalities

尿路异常的遗传起源和并发症

• 批准号: 9136794
• 负责人: JONATHAN M. BARASCH
• 金额: $ 120万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-24 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9136794
• 关键词: Accounting; Address; Benign; Child; Chronic Kidney Failure; Cicatrix; Collaborations; Communities; Complement; Congenital Abnormality; Defect; Development; Education; Educational workshop; Fever; Genetic; Genomic approach; Human; Inbred Strains Mice; Injury; Intercalated Cell; Kidney; Link; Maps; Methods; Minority Outreach Program; Modeling; Molecular Abnormality; Mutant Strains Mice; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Obstruction; Pathogenesis; Physicians; Pilot Projects; Prevention; Proteins; Recurrence; Research; Research Personnel; Research Project Grants; Role; SECTM1 gene; Scientist; Series; Signal Transduction; Structural defect; Training Programs; Universities; Urethra; Urinary tract; Urinary tract infection; Urogenital Sinus; Urology; Vesico-Ureteral Reflux; antimicrobial; cohort; data sharing; exome sequencing; experience; genome wide association study; improved; innovation; interdisciplinary approach; mouse model; multidisciplinary; nephrogenesis; next generation; public health relevance; rare variant; student training; success; urinary tract obstruction; urologic

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.

描述，总体（由申请人提供）：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群经验丰富的研究人员，具有长期的生产性合作记录，以解决良性泌尿外科的主要问题。囊泡排回流，后尿道瓣和相关形式的尿路 障碍物是人类常见的先天缺陷，儿童的慢性肾衰竭占20％。肾脏损害可能是由于固有的遗传异常会损害肾脏发生和输尿管功能，或者可能与与复发性尿路相关的疤痕有关。该中心将采用多学科方法来解决发展缺陷的起源及其在人类和小鼠模型中的并发症的起源。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将采用一种综合的基因组学方法，通过检查GWAS，CNV分析和外显子组测序方法可以发现的常见变体和稀有变体之间的相互作用，以阐明人类中VUR的发病机理。项目2将研究泌尿生殖器窦在尿道瓣后瓣的发生中的作用，并使用缺乏SALL1和RA信号的小鼠突变体的障碍物，这两种突变体都显示出阻塞。项目3将研究由α插入细胞分泌的结构缺陷和抗菌蛋白在尿路感染和肾脏损伤发展中的相互作用。这些项目 旨在通过在人类同龄人群后尿道瓣膜（飞行员1）中进行外显子组测序来发现罕见突变的创新试点建议，并通过在近育小鼠菌株中进行GWAS来倾向于尿路感染。 （飞行员2）。这些项目的科学目标是高度互连的，需要大力交流思想，无缝数据共享和多学科的协作努力，以取得成功。因此，该项目的一个核心主题是作为泌尿外科研究人员之间的协作活动和数据共享的模型，通过这些项目，我们将开发泌尿外科社区中科学发现的模型。最后，我们的奥布莱恩中心（O'Brien Center）主要着重于对泌尿外科研究的下一代临床医生的教育，包括年度研讨会，每两个月研讨会系列，夏季学生培训计划和少数派外展计划。我们还将使用机会池机制与NIDDK P20计划中心和K12 Kure中心进行互动，以吸引新的研究人员研究良性泌尿外科中的重要问题。