Variant Validation Core

变体验证核心

基本信息

批准号：
10747721
负责人：
JEFFREY H MINER
金额：
$ 27.38万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10747721
关键词：
Affect Amino Acid Sequence Amino Acids Benign Biological Assay CRISPR/Cas technology Cell Culture Techniques Chronic Chronic Kidney Failure Classification Code Complex Cultured Cells DNA Diagnosis Disease Etiology Exons Family Family Planning Founder Generation Gene Expression Genes Genetic In Vitro Kidney Kidney Diseases Link Mediating Mendelian disorder Modeling Mus Mutation Pathogenesis Pathogenicity Pathology Patients Proteins RNA RNA Splicing Research Personnel Resources Services Silicon Dioxide Single Nucleotide Polymorphism Symptoms Testing Time Universities Validation Variant Washington base clinical care cost effective cost effectiveness design developmental disease exome sequencing experimental study genetic disorder diagnosis genome sequencing genome wide association study genome-wide improved in silico in vitro Assay in vivo mouse genome mouse model protein function research study trafficking variant of unknown significance whole genome

项目摘要

Res-Core-001 (034) Project Summary The widespread and increasing use of targeted kidney gene panels, whole exome sequencing, and whole genome sequencing to investigate the genetic bases for chronic kidney disease and other kidney disorders has led to a much better understanding of the etiology of monogenic diseases. These approaches have provided patients with clear genetic diagnoses and in many cases have led to improved clinical care. In addition, having a genetic diagnosis has allowed patients to consider informing their relatives that they might also be affected. But there are many single nucleotide variants that have been discovered that are neither clearly pathogenic nor clearly benign; these are termed variants of uncertain significance (VUS). The aim of the proposed Variant Validation Core (VVC) is to investigate VUS discovered in patients with kidney disease or a kidney developmental disorder for potential pathogenicity. The WC will assist users in the efficient and cost-effective determination of the potential for pathogenicity of DNA/RNA/protein variants discovered in patients that cannot be classified as pathogenic or benign. The VVC will use in silica and cell culture approaches to assay protein function, RNA splicing, and gene expression by comparing wild-type to variants. In addition, CRISPR/Cas9- mediated gene editing will be used to generate appropriate mouse models carrying VUS; these will be analyzed for kidney disease or disorders. The experimental approach for each VUS brought to the VVC by a user will be tailored for 1) the particular gene and protein that are potentially involved; and 2) the particular disease or disorder that would likely develop if the VUS is indeed pathogenic. The VVC will be a valuable national resource for both clinicians and researchers who find VUS as part of routine clinical care or in larger research studies aimed at defining the genetic bases for diverse kidney diseases. The results of the experiments carried out by the VVC will be directly relevant to patient diagnosis and may be informative for clinical care, thus potentially impacting both patients and their families. The VVC will interact with the other O'Brien Cores at Washington University and will coordinate with the National O'Brien Consortium and Steering Committee to provide the highest quality services for users.

res-core-001（034）项目摘要靶向肾脏基因面板，整个外显子组测序以及整个基因组测序的广泛使用和越来越多的使用，以研究慢性肾脏疾病和其他肾脏疾病的遗传碱基，这使人们对单基因疾病的病因有了更好的了解。这些方法为患者提供了明确的遗传诊断，并且在许多情况下导致了改善的临床护理。此外，拥有遗传诊断已使患者可以考虑通知其亲戚也可能受到影响。但是，已经发现许多单核苷酸变体既不明确，也不明确良性。这些称为不确定意义（VU）的变体。提出的变体验证核心（VVC）的目的是研究在肾脏疾病患者或肾脏发育障碍中发现的VUS，以实现潜在的致病性。 WC将帮助用户有效且具有成本效益的确定在无法归类为致病性或良性的患者中发现的DNA/RNA/蛋白质变异的潜在。 VVC将在二氧化硅和细胞培养方法中使用，通过将野生型与变体进行比较，分析蛋白质功能，RNA剪接和基因表达。此外，将使用CRISPR/CAS9-介导的基因编辑来生成携带VUS的合适的小鼠模型。这些将分析肾脏疾病或疾病。用户将每种VUS带给VVC的VUS的实验方法将针对1）可能涉及的特定基因和蛋白质； 2）如果VUS确实具有致病性，可能会发展的特定疾病或疾病。 VVC将成为临床医生和研究人员的宝贵国家资源，他们认为VU是常规临床护理的一部分或旨在定义各种肾脏疾病的遗传基础的大型研究的一部分。 VVC进行的实验结果将与患者诊断直接相关，并且可能对临床护理有用，从而可能影响患者及其家人。 VVC将与华盛顿大学的其他奥布莱恩核心互动，并将与国家奥布莱恩财团和指导委员会协调，为用户提供最高质量的服务。