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)是一种退行性关节疾病,其特征在于关节软骨损伤和
软骨下骨的结构,是世界上最常见的关节疾病1。许多基因位点2和
环境因素如生物力学应力3 -8与关节健康有关,
基因表达的调节在介导疾病的道路上。然而,这些因素如何相互作用,
OA的发病机制尚不清楚。评估基因与环境相互作用对基因调控的影响
在人类OA发展的背景下,这里提出的工作将研究基因的个体间变异,
表达对软骨细胞(软骨的初级细胞)中的生物力学应力的响应。具体而言,在Aim
1,我将使用iPSC衍生的免疫组织化学方法表征应激和对照软骨细胞中的基因表达。
OA的生物力学应变模型。我优化了OA 9 -12的循环拉伸应变处理方案模型
用于iPSC衍生的软骨细胞13。我进一步将这些方法应用于小组中的三个人
的58个约鲁巴人(缩写:YRI)人iPSC系14。使用来自本研究的批量和单细胞RNA-seq数据,
在实验中,我已经确定了生物力学应变条件之间的差异基因表达模式。
在这项工作的继续中,我将使所有58个YRI iPSC系分化成软骨细胞,并表征其体积。
以及应变和对照软骨细胞中的单细胞转录。在目标2中,我将确定生物力学应变
动态表达数量性状基因座(eQTL)在分化的软骨细胞。我使用的数据来自
一个小规模的试点研究,以建立可行的应变模型的OA定位eQTL。我要用RNA-
目标1中收集的seq数据用于鉴定在处理条件之间效果不同的动态eQTL,同时
评估和解释分化效率的差异和对周期性
拉伸应变在目标3中,我将整合定位的动态eQTL和全基因组关联研究(GWAS)
和表观遗传数据,以更好地了解遗传位点变异的功能后果
与OA有关。我将测试我的动态eQTL在已发表的eQTL中的富集和共定位。
显著的OA GWAS基因座15,以确定OA遗传关联是否可以通过环境影响OA风险,
特异性基因调控我还将使用来自
基因型-组织表达项目16.最后,我将收集DNA甲基化和染色质可及性数据
来评估这些分子表型在生物力学应力下的变化
并可能介导转录变化。总的来说,我的工作将阐明如何的遗传基础
生物力学应力影响人类关节健康。更广泛地说,我的项目将加深我们对
基因与复杂疾病的关联如何通过基因与环境的相互作用来介导。
同时,这项工作将为我提供丰富的机会来发展我的湿实验室和计算能力。
研究技能,同时受益于广泛的合作者和导师的支持。
项目成果
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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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