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Determing the genetic basis of responses to biomechanical strain in an in vitro model of osteoarthritis

确定骨关节炎体外模型中生物力学应变反应的遗传基础

基本信息

批准号：
10538602
负责人：
Anthony Hung
金额：
$ 5.27万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10538602
关键词：
Abbreviations Accounting Affect Biochemical Biological Biology Biomechanics Bone structure Cell Culture Techniques Cell Line Cells Chondrocytes Chromatin Chronic Complex DNA Methylation Data Degenerative polyarthritis Development Disease Disease Progression Disparity Environmental Risk Factor Epigenetic Process Gene Expression Gene Expression Profile Gene Expression Regulation Genes Genetic Genetic Transcription Genetic Variation Genomics Genotype-Tissue Expression Project Health Heritability Heterogeneity Homeostasis Human In Vitro Individual Individual Differences Joints Link Maps Measures Mediating Mentors Methods Modeling Nature Onset of illness Pain Pathogenesis Pathway interactions Pattern Periodicity Phenotype Pilot Projects Process Publishing Quantitative Trait Loci Replacement Arthroplasty Research Resort Risk Sampling Specificity Stimulus Stress Structure System Testing Time Tissue-Specific Gene Expression Tissues Trauma Treatment Protocols United States Variant Work arthropathies articular cartilage cartilage cell disability experimental study gene environment interaction genetic association genome wide association study genomic locus improved in vitro Model induced pluripotent stem cell insight inter-individual variation joint inflammation joint loading mechanical load molecular phenotype response risk variant single-cell RNA sequencing skills subchondral bone tissue culture transcriptome sequencing

项目摘要

Osteoarthritis (OA), a degenerative joint disorder characterized by articular cartilage damage and alterations to the structure of subchondral bone, is the most common joint disease worldwide1. Numerous genetic loci2 and environmental factors such as biomechanical stress3–8 have been associated with joint health and may modulate the regulation of gene expression on the road to mediate disease. However, how these factors interact to initiate OA pathogenesis is still unclear. To evaluate the effects of gene-by-environment interactions on gene regulation in the context of human OA development, the work proposed here will study inter-individual variation in gene expression responses to biomechanical stress in chondrocytes, the primary cells of cartilage. Specifically, in Aim 1, I will characterize gene expression in stressed and control chondrocytes using an iPSC-derived biomechanical strain model of OA. I have optimized a cyclic tensile strain treatment regimen model of OA9–12 for use on iPSC-derived chondrocytes13. I have further applied these methods to three individuals from a panel of 58 Yoruba (abbreviation: YRI) human iPSC lines14. Using bulk and single-cell RNA-seq data from this experiment, I have identified patterns of differential gene expression between biomechanical strain conditions. In the continuation of this work, I will differentiate all 58 YRI iPSC lines into chondrocytes and characterize bulk and single-cell transcription in strained and control chondrocytes. In Aim 2, I will identify biomechanical strain dynamic expression quantitative trait loci (eQTLs) in differentiated chondrocytes. I have used data from a small-scale pilot study to establish the viability of this strain model of OA for mapping eQTLs. I will use RNA- seq data collected in Aim 1 to identify dynamic eQTLs that vary in effect between treatment conditions while assessing and accounting for disparities in differentiation efficiency and heterogeneity in the response to cyclic tensile strain. In Aim 3, I will integrate mapped dynamic eQTLs with genome-wide association study (GWAS) and epigenetic data to better understand the functional consequences of variation at genetic loci associated with OA. I will test for enrichment and colocalization of my dynamic eQTLs among published significant OA GWAS loci15 to determine if OA genetic associations could influence OA risk through context- specific gene regulation. I will also evaluate the tissue-specificity of my dynamic eQTLs using data from the Genotype-Tissue Expression Project16. Finally, I will collect DNA methylation and chromatin accessibility data from my in vitro system to assess how these molecular phenotypes change in response to biomechanical stress and potentially mediate transcriptional changes. Overall, my work will elucidate the genetic basis of how biomechanical stress impacts human joint health. More broadly, my project will deepen our understanding of how genetic associations with complex diseases may be mediated through gene-by-environment interactions. At the same time, this work will provide me abundant opportunities to grow my wet lab and computational research skills while benefitting from the support of a wide group of collaborators and mentors.

骨关节炎（OA），一种以关节软骨损伤和改变为特征的退行性关节疾病