Center for Undiagnosed Pediatric Renal and Urogenital Disorders

描述（由申请人提供）：肾脏和泌尿生殖系统疾病是一个主要的健康负担，仍然知之甚少，并且通常在临床上难以治疗。同样重要的是，这些器官的解剖缺陷经常与严重的、危及生命的全身综合征相关，这些综合征可能仍然无法诊断。我们中心的使命是汇集尖端的基因组学工具和解释性生物测定，以加强和加速这些疾病的分子诊断。我们提出了三个主要活动：a）从杜克诊所招募的家族中进行表型、招募和生物库样本，但也从美国各地的先天性肾脏和泌尿生殖系统解剖缺陷患者中转介给我们，这些患者未能通过传统手段进行分子诊断; B）进行外显子组分析，c）对所发现的具有预测临床价值的变异的子集进行功能性测试，并在体外开发（原代细胞）和体内工具（斑马鱼和小鼠）来模拟这种变化的影响; d）综合混合临床和研究数据，与临床管理团队合作，可以为患者的未来管理和干预提供信息。同时，我们提出两项高风险的试点活动，旨在改善 遗传学和新的治疗线索的发现。首先，我们将开发快速鉴定新的斑马鱼肾突变体的技术，这可以加速鉴定在肾脏发育中重要的新基因。第二，我们将建立新的平台，用于在斑马鱼肾脏疾病模型中筛选先导化合物（包括以前建立的和作为我们中心的一部分新开发的）。最后，由于我们的中心代表了患者，医生和基础科学家之间的合作，我们将开发信息平台，以促进外显子组范围的研究和临床数据向医生和患者家属的传播，并从这个社区迭代学习如何最好地实施这些信息，以改善医疗保健。总之，我们的中心将提供该领域急需的利基，可能会提高医生和患者对肾脏和泌尿生殖系统综合征的知识基础，并将为加速诊断，管理和治疗提供基础。

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.