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.

资源核心-001 (034) 项目概要靶向肾脏基因组、全外显子组测序和全基因组测序的广泛且越来越多的使用来研究慢性肾脏病和其他肾脏疾病的遗传基础，使得人们对单基因疾病的病因学有了更好的了解。这些方法为患者提供了明确的基因诊断，并在许多情况下改善了临床护理。此外，进行基因诊断使患者可以考虑告知其亲属他们也可能受到影响。但已发现的许多单核苷酸变异既不是明显的致病性，也不是明显的良性。这些被称为意义不确定的变体（VUS）。拟议的变异验证核心 (VVC) 的目的是调查在肾脏疾病或肾脏发育障碍患者中发现的 VUS 的潜在致病性。 WC 将帮助用户高效、经济地确定在无法归类为致病或良性的患者中发现的 DNA/RNA/蛋白质变异的潜在致病性。 VVC 将使用二氧化硅和细胞培养方法，通过比较野生型与变异体来测定蛋白质功能、RNA 剪接和基因表达。此外，CRISPR/Cas9介导的基因编辑将用于生成携带VUS的合适小鼠模型；将对其进行肾脏疾病或病症分析。用户带到 VVC 的每个 VUS 的实验方法将针对 1) 可能涉及的特定基因和蛋白质进行定制； 2) 如果 VUS 确实具有致病性，则可能出现的特定疾病或病症。对于临床医生和研究人员来说，VVC 将成为宝贵的国家资源，他们将 VUS 作为常规临床护理或旨在确定不同肾脏疾病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，并可能为临床护理提供信息，从而可能对患者及其家人产生影响。 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联盟和指导委员会协调，为用户提供最优质的服务。