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

• 批准号: 10706477
• 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
• 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/10706477
• 关键词: 3-Dimensional; Acetylation; Address; Affect; Alleles; 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; Genome; Genomics; Goals; Histones; Human; Human Genome; Individual; Joints; Knee; Knee Osteoarthritis; Knock-out; 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

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 尽管膝骨关节炎（OA）在全球范围内患病率很高，但治疗选择仅限于症状治疗 管理和全关节置换术在很大程度上是因为驱动膝关节骨关节炎的机制仍然很差 明白了。全基因组关联研究（GWAS）表明非编码遗传变异是一个主要的遗传变异。 导致膝关节 OA 疾病风险的因素；然而，人类基因组的LD结构， 转录调控，以及缺乏基因组可编辑和生物学精确的系统来研究 OA 造成了一个瓶颈，阻碍了我们将 GWAS 研究结果转化为新疗法的能力。这 该提案的总体目标是识别假定的膝关节 OA 风险变异，并将其映射到目标 基因，并量化它们对软骨细胞的表型影响。我们将确定激活的监管区域 响应软骨退化（目标 1），将调控位点和 GWAS 变异映射到其目标基因 （目标 2），并使用膝关节 OA 相关变异的离体模型量化表型影响 软骨细胞 OA 表型（目标 3）。这项工作将打破膝关节 OA 遗传学的现有障碍，改善 我们对膝关节骨关节炎的机制了解，并为进一步研究和治疗提供新的危险基因 发展。