Center for Undiagnosed Pediatric Renal and Urogenital Disorders

未确诊小儿肾脏和泌尿生殖疾病中心

基本信息

批准号：
9135895
负责人：
NICHOLAS KATSANIS
金额：
$ 5.36万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9135895
关键词：
Advisory Committees Alleles Back Basic Science Biological Assay Biological Models Biology Cells Child Childhood Clinic Clinical Clinical Data Clinical Management Clinical Research Clinical Treatment Collaborations Communities Complex Data Databases Defect Detection Development Diagnosis Diagnostic Disease Dysmorphology Experimental Models Failure Family Family member Foundations Frequencies Future Generations Genes Genetic Genetic screening method Genitourinary system Genomics Goals Health Healthcare Healthcare Systems Hybrids In Vitro Individual Infant Intervention Investigation Kidney Kidney Diseases Lead Learning Lesion Life Location Medical Mission Modeling Molecular Diagnosis Mus Mutation Neonatal Nephrology Organ Outcome Pathway interactions Patient Care Patients Phenotype Physicians Population Primary Health Care Principal Investigator Procedures Provider Recommendation Recruitment Activity Recurrence Relative (related person)Research Role Sampling Scientist Secure Specialist Staging Syndrome System Technology Testing Therapeutic United States Universities Variant Work Zebrafish bench to bedside biobank clinical investigation clinical phenotype cost exome exome sequencing experience gene discovery genome sequencing genome-wide genomic tools high risk improved in vivo innovation knowledge base multidisciplinary mutant neonate nephrogenesis novel novel therapeutics prenatal public health relevance rapid diagnosis research clinical testing screening stem tool

项目摘要

DESCRIPTION (provided by applicant): Disorders of the renal and urogenital system represent a major health burden, remain poorly understood, and are often clinically intractable. Of equal importance, anatomical defects in these organs are associated frequently with serious, life-threatening systemic syndromes that can remain refractive to diagnosis. The mission of our Center is to bring together cutting-edge genomics tools and interpretative biological assays to potentiate and accelerate the molecular diagnosis of these disorders. We propose three major activities: a) to phenotype, recruit and biobank samples from families recruited at the Duke clinics but also referred to us from across the United States with congenital anatomical renal and urogenital defects that have failed to secure a molecular diagnosis through traditional means; b) to perform exome (and ultimately genome) sequencing on appropriate family members; c) to functionally test a subset of discovered variation that is of predicted clinical value and to develop in vitro (primary cells) and in vivo tools (zebrafish and mouse) to model the effects of such variation; d) to synthesize hybrid clinical and research data that, in collaboration with the clinical management team, can inform future management and intervention in patients. In parallel, we propose two high-risk pilot activities aimed at improving both the genetics and the discovery of novel therapeutic leads. First, we will develop the technology for the rapid identification of new zebrafish renal mutants that can accelerate the identification of new genes important in kidney development. Second, we will generate new platforms for the screening of lead compounds in zebrafish models of renal disease (both previously established and newly-developed as part of our Center). Finally, because our Center represents a collaboration between patients, physicians and basic scientists, we will develop information platforms to facilitate the dissemination of exome-wide research and clinical data to both physicians and patient families, and to learn iteratively from this community about how to best implement such information to improve health care. Taken together, our Center will provide a much-needed niche in the field, will likely improve the knowledge base of both physicians and patients about syndromes with a renal and urogenital component, and will provide the foundation for accelerated diagnosis, management and treatment.

描述（由申请人提供）：肾脏和泌尿生殖系统疾病是主要的健康负担，但人们对此仍知之甚少，并且在临床上常常难以治疗。同样重要的是，这些器官的解剖缺陷常常与严重的、危及生命的全身综合征相关，而这些综合征可能仍然无法诊断。我们中心的使命是将尖端的基因组学工具和解释性生物测定结合在一起，以加强和加速这些疾病的分子诊断。我们提出了三项主要活动：a) 对在杜克诊所招募的家庭进行表型分析、招募和生物库样本，但也向我们推荐了来自美国各地的患有先天性肾脏和泌尿生殖系统缺陷的家庭，这些缺陷无法通过传统手段进行分子诊断; b) 对适当的家庭成员进行外显子组（最终是基因组）测序； c) 对已发现的具有预测临床价值的变异子集进行功能测试，并开发体外（原代细胞）和体内工具（斑马鱼和小鼠）来模拟此类变异的影响； d) 与临床管理团队合作，综合混合临床和研究数据，为未来的患者管理和干预提供信息。与此同时，我们提出两项高风险试点活动，旨在改善遗传学和新治疗线索的发现。首先，我们将开发快速鉴定新斑马鱼肾脏突变体的技术，该技术可以加速鉴定对肾脏发育重要的新基因。其次，我们将创建新的平台，用于筛选斑马鱼肾脏疾病模型中的先导化合物（包括先前建立的和作为我们中心的一部分新开发的平台）。最后，由于我们的中心代表患者、医生和基础科学家之间的合作，我们将开发信息平台，以促进向医生和患者家属传播全外显子组研究和临床数据，并从这个社区反复学习如何最好地利用这些信息来改善医疗保健。总而言之，我们的中心将提供该领域急需的利基，可能会改善医生和患者有关肾脏和泌尿生殖系统综合征的知识库，并将为加速诊断、管理和治疗奠定基础。