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:
- 金额:$ 5.27万
- 依托单位:
- 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:
- 关键词:AbbreviationsAccountingAffectBiochemicalBiologicalBiologyBiomechanicsBone structureCell Culture TechniquesCell LineCellsChondrocytesChromatinChronicComplexDNA MethylationDataDegenerative polyarthritisDevelopmentDiseaseDisease ProgressionDisparityEnvironmental Risk FactorEpigenetic ProcessGene ExpressionGene Expression ProfileGene Expression RegulationGenesGeneticGenetic TranscriptionGenetic VariationGenomicsGenotype-Tissue Expression ProjectHealthHeritabilityHeterogeneityHomeostasisHumanIn VitroIndividualIndividual DifferencesJointsLinkMapsMeasuresMediatingMentorsMethodsModelingNatureOnset of illnessPainPathogenesisPathway interactionsPatternPeriodicityPhenotypePilot ProjectsProcessPublishingQuantitative Trait LociReplacement ArthroplastyResearchResortRiskSamplingSpecificityStimulusStressStructureSystemTestingTimeTissue-Specific Gene ExpressionTissuesTraumaTreatment ProtocolsUnited StatesVariantWorkarthropathiesarticular cartilagecartilage celldisabilityexperimental studygene environment interactiongenetic associationgenome wide association studygenomic locusimprovedin vitro Modelinduced pluripotent stem cellinsightinter-individual variationjoint inflammationjoint loadingmechanical loadmolecular phenotyperesponserisk variantsingle-cell RNA sequencingskillssubchondral bonetissue culturetranscriptome 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
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Anthony Hung其他文献
Anthony Hung的其他文献
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{{ truncateString('Anthony Hung', 18)}}的其他基金
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
- 批准号:
10156429 - 财政年份:2021
- 资助金额:
$ 5.27万 - 项目类别:
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
- 批准号:
10348171 - 财政年份:2021
- 资助金额:
$ 5.27万 - 项目类别:
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