Genome and epigenome editing of induced pluripotent stem cells for investigating osteoarthritis risk alleles
诱导多能干细胞的基因组和表观基因组编辑用于研究骨关节炎风险等位基因
基本信息
- 批准号:10707979
- 负责人:
- 金额:$ 17.11万
- 依托单位:
- 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:2022-09-22 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAffectAllelesAnabolismAutomobile DrivingBiochemicalBiological ModelsCRISPR/Cas technologyCartilageCartilage MatrixCartilage injuryCatabolismChondrocytesChromosome 8ComplexCytoskeletal ProteinsDNA MethylationDataDegenerative polyarthritisDevelopmentEpigenetic ProcessEquilibriumEventFutureGene FrequencyGenesGeneticGenetic PolymorphismGenetic RiskGenetic VariationGenomeGenotypeGoalsHip OsteoarthritisHistologyHomeostasisHumanHuman EngineeringHypertrophyImmunohistochemistryIn VitroIntronsKnock-outLeadLinkMechanical StressMechanicsMediatingMethylationMinorMolecularPathologicPathway interactionsPatientsPhenotypePhysiologicalPhysiologyPlayProcessProductionQuantitative Trait LociRegulationRegulatory PathwayReportingRiskRoleSecondary toSignal PathwaySignal TransductionSingle Nucleotide PolymorphismSpecimenSystemTestingTissue EngineeringTissuesUnited Kingdomarticular cartilagebiobankcartilage developmentcell typecohortcomparison controldisabilityepigenetic regulationepigenomeepigenome editinggene regulatory networkgenetic variantgenome editinggenome wide association studyin vitro Modelinduced pluripotent stem cellinterestmechanical loadmechanical propertiesmechanotransductionnew therapeutic targetnovelplectinpreventresponserisk variantsingle-cell RNA sequencingstem cellstranscriptometranscriptome sequencingvariant of interest
项目摘要
Abstract
Genome wide association studies (GWAS) in large cohorts have identified and replicated robust single
nucleotide polymorphisms (SNPs) with a strong association to osteoarthritis (OA) development. While many
SNPs have been identified as risks for OA development, a mechanistic understanding of their role in cartilage
homeostasis and mechanobiology has remained elusive. We propose to use a novel in vitro system
combining genome editing of human induced pluripotent stem cells (iPSCs) and cartilage tissue engineering
for studying the functional effect of identified OA SNPs on the biochemical and mechanical properties of
articular cartilage. In preliminary data, we reported a functional characterization of rs11780978 in which we
identified an expression quantitative trait locus (eQTL) operating on the gene PLEC in the cartilage of patients
with OA. Our primary hypothesis is that OA-associated SNP rs11780978 results in reduced expression of
PLEC in chondrocytes secondary to altered epigenetic regulation at this locus. Using CRISPR-Cas9 and
dCas9TET-mediated genome editing, we will examine the role of genetic and epigenetic modulation (PLEC
knockout and hypomethylation of the functional region) on the chondrogenic differentiation of hiPSCs.
Furthermore, we propose that reduced production of plectin due to this SNP alters the response of
chondrocytes to mechanical stress under physiologic or pathologic conditions. This tissue-engineering
approach provides a model system that can be used in future studies to examine specific mechanistic
hypothesis on the link between OA-associated SNPs and the regulation of chondrocyte physiology.
Identification of these mechanisms will hopefully lead to new therapeutic targets for preventing or slowing OA
progression.
抽象的
大型队列中的基因组广泛关联研究(GWAS)已鉴定并复制了可靠的单一
核苷酸多态性(SNP)与骨关节炎(OA)发育有很强的关联。而很多
SNP已被确定为OA开发的风险,一种机械理解其在软骨中的作用
稳态和机械生物学仍然难以捉摸。我们建议使用一种新颖的体外系统
结合人类诱导多能干细胞(IPSC)和软骨组织工程的基因组编辑
用于研究已鉴定的OA SNP对生化和机械性能的功能效应
关节软骨。在初步数据中,我们报告了RS11780978的功能表征,其中我们
鉴定出在患者软骨中在基因PLEC上作战的表达定量性状基因座(EQTL)
与OA。我们的主要假设是,与OA相关的SNP RS11780978导致表达降低
在该基因座的表观遗传调节变化的软骨细胞中PLEC。使用CRISPR-CAS9和
DCAS9TET介导的基因组编辑,我们将研究遗传和表观遗传调节的作用(PLEC
功能区域的敲除和甲基化)在HIPSC的软骨分化上。
此外,我们提出,由于SNP,降低了蛋白质的产生,改变了
在生理或病理状况下机械应力的软骨细胞。这种组织工程
方法提供了一个模型系统,可以在以后的研究中使用该系统来检查特定的机理
关于OA相关SNP与软骨细胞生理学调节之间联系的假设。
这些机制的识别将导致预防或放缓OA的新治疗靶点
进展。
项目成果
期刊论文数量(0)
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Farshid Guilak其他文献
Farshid Guilak的其他文献
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{{ truncateString('Farshid Guilak', 18)}}的其他基金
Synthetic Chronogenetic Gene Circuits for Circadian Cell Therapies
用于昼夜节律细胞疗法的合成计时基因电路
- 批准号:
10797183 - 财政年份:2023
- 资助金额:
$ 17.11万 - 项目类别:
2023 Cartilage Biology and Pathology Gordon Research Conference and Gordon Research Seminar
2023年软骨生物学与病理学戈登研究会议暨戈登研究研讨会
- 批准号:
10605625 - 财政年份:2022
- 资助金额:
$ 17.11万 - 项目类别:
Genome and epigenome editing of induced pluripotent stem cells for investigating osteoarthritis risk alleles
诱导多能干细胞的基因组和表观基因组编辑用于研究骨关节炎风险等位基因
- 批准号:
10532032 - 财政年份:2022
- 资助金额:
$ 17.11万 - 项目类别:
Deconstructing Cartilage Mechanotransduction by Piezo Channels
通过压电通道解构软骨机械传导
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10533155 - 财政年份:2022
- 资助金额:
$ 17.11万 - 项目类别:
SMART stem cells that autonomously down-modulate TFG-β signaling for Articular Cartilage Repair
SMART 干细胞自主下调 TFG-β 信号传导以修复关节软骨
- 批准号:
10371823 - 财政年份:2022
- 资助金额:
$ 17.11万 - 项目类别:
Genetically-engineered stem cells for self-regulating arthritis therapy
用于自我调节关节炎治疗的基因工程干细胞
- 批准号:
10630757 - 财政年份:2022
- 资助金额:
$ 17.11万 - 项目类别:
Genetically-engineered stem cells for self-regulating arthritis therapy
用于自我调节关节炎治疗的基因工程干细胞
- 批准号:
10598619 - 财政年份:2022
- 资助金额:
$ 17.11万 - 项目类别:
Genetically-engineered stem cells for self-regulating arthritis therapy
用于自我调节关节炎治疗的基因工程干细胞
- 批准号:
10434316 - 财政年份:2022
- 资助金额:
$ 17.11万 - 项目类别:
SMART stem cells that autonomously down-modulate TFG-β signaling for Articular Cartilage Repair
SMART 干细胞自主下调 TFG-β 信号传导以修复关节软骨
- 批准号:
10590752 - 财政年份:2022
- 资助金额:
$ 17.11万 - 项目类别:
Genetically-engineered stem cells for self-regulating arthritis therapy
用于自我调节关节炎治疗的基因工程干细胞
- 批准号:
10831324 - 财政年份:2022
- 资助金额:
$ 17.11万 - 项目类别:
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