Leadership Implementation Project

领导力/实施项目 项目摘要 这项申请提出了华盛顿大学圣路易斯医学院(WUSM)的模式生物 筛查核心(WuMOSC)作为NIH未诊断疾病网络(UDN)第二阶段的关键资产。这个 WuMOSC将评估UDN临床站点每年确定的200个遗传变异的致病性 其他未诊断的参与者通过利用以下四个模式生物的最佳组合 和基于细胞的资源核心：1)线虫，2)果蝇，3)斑马鱼，4)人类多能干细胞 细胞(HPSCs)。这些模型系统的组合允许极快且具有成本效益的变体 在线虫中的评估，以及在hPSCs中对动物中不保守的基因和变异体的评估 模式生物，同时保持果蝇和斑马鱼模型的既定优势。一个 已经组建了经验丰富的领导团队，利用合作研究环境， WUSM，包括McDonnell基因组研究所的专业知识和出色的WUSM临床合作伙伴 这构成了拟议的UDN第二阶段WUSM排序中心和临床现场应用， 分别进行了分析。使用成熟、尖端和新颖的生物信息学方法，结合深思熟虑的 考虑到每一种模式生物的优点和局限性，已经制定了仔细的评估计划 确定指定变异体的假定致病性，并确定它们的优先顺序，以便进一步 由资源核心进行评估。四个研究核心的领导人在以下方面拥有丰富的专业知识 相关模型系统，目前正在采用拟议的先进遗传方法 (CRISPR/Cas9敲入、组织特异性RNAi和过度表达，以及检测突变变异体mRNA 救援)和广泛的表型分析，以评估人类基因变异对基因产物功能的影响。 UDN临床站点、指导委员会和协调委员会将频繁接待 通过行政核心的活动，通报世界海关组织的计划和成果， 它还将把获得的模式生物专业知识传播给更广泛的NIH和其他研究 社区。因此，wumosc将对世界卫生组织的诊断工作产生极大的影响。 通过生物信息学和实验筛选在以下背景下可能导致疾病的变异 疾病特有的表型。

Leadership/Implementation Project Project Summary This application proposes the Washington University in St. Louis School of Medicine (WUSM) Model Organism Screening Core (wuMOSC) as a key asset for Phase II of the NIH Undiagnosed Diseases Network (UDN). The wuMOSC will evaluate the pathogenicity of 200 genetic variants per year identified by UDN Clinical Sites in otherwise undiagnosed participants by leveraging the optimal combination of the following four model organism and cell-based Resource Cores: 1) C. elegans, 2) Drosophila, 3) zebrafish, and 4) human pluripotent stem cells (hPSCs). The combination of these model systems allows for extremely rapid and cost-effective variant evaluation in C. elegans, and evaluation in hPSCs of genes and variants that are not conserved in the animal model organisms, while maintaining the established advantages of the Drosophila and zebrafish models. An experienced Leadership Team has been assembled that harnesses the collaborative research environment at WUSM, including the expertise of the McDonnell Genome Institute, and the superb WUSM clinical partners that constitute the proposed UDN Phase II WUSM Sequencing Center and Clinical Site applications, respectively. Using proven, cutting-edge, and novel bioinformatic approaches, combined with thoughtful consideration of the advantages and limitations of each model organism, a careful assessment plan has been defined for determining the putative pathogenicity of nominated variants and prioritizing them for further evaluation by the Resource Cores. The leaders of the four Research Cores have significant expertise in the relevant model system, and are currently employing the proposed advanced genetic approaches (CRISPR/Cas9 knock-in, tissue-specific RNAi and overexpression, and testing variant mRNA for null mutant rescue) and extensive phenotypic analysis to assess human gene variants for effect on gene product function. The UDN Clinical Sites, Steering Committee, and Coordinating Committee will receive frequent communications regarding plans and results of the wuMOSC, through the activity of the Administrative Core, which will also disseminate acquired model organism expertise to the wider NIH and other research communities. Therefore, the wuMOSC will have an exceptionally high impact on the diagnostic efforts of the UDN by bioinformatically and experimentally screening potential disease-causing variants in the context of disease-specific phenotypes.