Identifying novel osteoarthritis risk genes using GWAS, chondrocyte genomics, and genome editing

使用 GWAS、软骨细胞基因组学和基因组编辑识别新的骨关节炎风险基因

基本信息

批准号：
10445527
负责人：
RICHARD F LOESER
金额：
$ 50.85万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445527
关键词：
3-Dimensional Acetylation Address Affect Automobile Driving Base Pairing Binding Bioinformatics Biology Cartilage Cartilage Matrix Cell model Chondrocytes Chromatin Chromatin Structure Computer Models Data Data Element Degenerative polyarthritis Development Dissection Engineering Enhancers Fibronectins Genes Genetic Genetic Transcription Genetic Variation Genomics Goals Histones Human Human Genome Individual Joints Knee Knee Osteoarthritis Knock-out Lead Linkage Disequilibrium Maps Measurement Measures Modeling Nature Nucleic Acid Regulatory Sequences Pathogenesis Phenotype Prevalence Process Protocols documentation RNA Regulatory Element Replacement Arthroplasty Research Resolution Rest Risk Structure System Techniques Time Tissues Transcriptional Regulation Translating Untranslated RNA Variant Work cartilage degradation causal variant cell type disorder risk genetic variant genome editing genome wide association study human disease improved novel response risk variant symptom management therapeutic development transcription factor transcription regulatory network

项目摘要

Project Abstract Despite the high global prevalence of knee osteoarthritis (OA), treatment options have been limited to symptom management and total joint replacement in large part because the mechanisms driving knee OA remain poorly understood. Genome-wide association studies (GWAS) suggest that non-coding genetic variation is a major contributor to knee OA disease-risk; however, the LD structure of human genomes, the long-range nature of transcriptional regulation, and the lack of genome-editable and biologically accurate systems in which to study OA have created a bottleneck that hinders our ability to translate GWAS findings into new treatments. The overall objective of this proposal is to identify putative causal knee OA risk variants, map them to their target genes, and quantify their phenotypic impact in chondrocytes. We will identify regulatory regions activated in response to cartilage degradation (Aim 1), map regulatory loci and GWAS variants to their target genes (Aim 2), and quantify the phenotypic impacts of knee OA-associated variants using an ex vivo model of the chondrocyte OA phenotype (Aim 3). This work will break down existing barriers in knee OA genetics, improve our mechanistic understanding of knee OA, and provide new risk genes for further study and therapeutic development.

项目摘要尽管膝关节骨关节炎（OA）的全球患病率很高，但治疗方案仍限于症状管理和总置换很大程度上是因为驾驶膝盖OA的机制保持较差理解。全基因组关联研究（GWAS）表明非编码遗传变异是主要的膝关节疾病风险的贡献者；但是，人类基因组的LD结构，是远程的性质转录调节，缺乏基因组编辑和生物学精确的系统来研究 OA创造了一种瓶颈，阻碍了我们将GWAS发现转化为新疗法的能力。这该建议的总体目的是确定假定的因果膝oa风险变体，将其映射到目标基因，并量化其在软骨细胞中的表型影响。我们将确定激活的监管区域为了响应软骨降解（AIM 1），将调节基因座和GWAS变体映射到目标基因（AIM 2），并使用该模型量化了膝关节OA相关变体的表型影响软骨细胞OA表型（AIM 3）。这项工作将打破膝关节遗传学的现有障碍，改善我们对膝盖OA的机械理解，并提供了新的风险基因，以进一步研究和治疗发展。