The role of microRNAs in cartilage homeostasis and osteoarthritis arthritis treatment
microRNA在软骨稳态和骨关节炎治疗中的作用
基本信息
- 批准号:9906170
- 负责人:
- 金额:$ 42.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-07-01 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAnimal ModelArthritisBioinformaticsCRISPR/Cas technologyCartilageCellsChondrocytesChondrogenesisDegenerative polyarthritisDevelopmental ProcessDiseaseDisease ProgressionEventExperimental ModelsExtracellular MatrixFamilyGene ExpressionGenesGrowthHigh Mobility Group ProteinsHistologicHomeostasisHumanIn VitroInflammatoryInterleukin-1 betaKnee jointKnockout MiceLifeLimb DevelopmentMaintenanceMesenchymalMicroRNAsMicroarray AnalysisMolecularMovementMusNeonatalNucleotidesOperative Surgical ProceduresPathogenesisPatternPharmaceutical PreparationsPhenotypePhysiologic OssificationPhysiological ProcessesPlayProcessRegulationRegulator GenesRegulatory PathwayReportingRoleSignal TransductionSurgical ModelsSurveysSynovial jointSystemTestingTherapeutic EffectTherapeutic InterventionTissuesUntranslated RNAWorkarthropathiesarticular cartilagebonecartilage developmentearly onsetexperimental studyinsightnovel therapeutic interventionoverexpressionpostnatalpreventprogramsskeletaltranscription factor
项目摘要
ABSTRACT
Chondrocytes play an important role in limb development, postnatal skeletal growth and in maintaining
cartilage tissues during adult life. Dysregulation of gene expression in chondrocytes is a key event in the
pathogenesis of osteoarthritis (OA). MicroRNAs are a family of noncoding RNAs that are evolutionarily
conserved and regulate gene expression by posttranscriptional mechanisms. Many miRs show tissue specific
expression patterns, suggesting that these miRs play a crucial role in tissue specific physiological or
developmental processes. However, chondrocyte specific miRs, their upstream molecular signals, and target
genes are only beginning to be identified. We and others reported that miR-140, a cartilage specific miRNA,
plays a critical role both in cartilage development and homeostasis while the reduced expression in OA
contributes to pathogenesis.
In our preliminary experiments, both strands of miR-455 (miR-455-5p and miR-455-3p) as well as miR-140
were identified as targets of Sox9, a main transcription factor for cartilage specific genes. Expression of miR-
455-5p/3p was down-regulated in human OA cartilage compared with normal cartilage. Using CRISPR/Cas9
system, we generated miR-455-5p/3p knockout mice. These mice showed a severe OA phenotype at 6 months.
Microarray analyses revealed a set of possible miR-455 target genes in chondrocytes, including HIF2A, which
is a key transcription factor in OA pathogenesis, and a target of both strands of miR455. Importantly, HIF2A
was strongly increased in almost all chondrocytes in articular cartilage of miR-455 null mice at 6 months.
These observations support the hypothesis that miR-455-5p/3p are critical regulators of cartilage
homeostasis and that changes in their expression and function play an important role in diseases affecting
articular cartilage. We propose the following specific aims:
Aim 1: Analyze the function of miR-455-5p/3p in OA pathogenesis using miR-455 KO mice and human
articular chondrocytes.
Aim 2: Identify in articular chondrocytes the direct miR-455-5p/3p downstream targets that regulate cartilage
homeostasis and OA pathogenesis.
Aim 3: Examine the therapeutic effects of intraarticular miR-455s administration in animal models of OA.
The proposed studies have the potential to reveal important new regulatory pathways that control
cartilage development and homeostasis and open new insight on disease mechanisms and therapeutic
interventions.
摘要
项目成果
期刊论文数量(0)
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会议论文数量(0)
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HIROSHI ASAHARA其他文献
HIROSHI ASAHARA的其他文献
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{{ truncateString('HIROSHI ASAHARA', 18)}}的其他基金
Mechano signals regulating tendon and ligament homeostasis
机械信号调节肌腱和韧带稳态
- 批准号:
10522344 - 财政年份:2022
- 资助金额:
$ 42.35万 - 项目类别:
Mechano signals regulating tendon and ligament homeostasis
机械信号调节肌腱和韧带稳态
- 批准号:
10707502 - 财政年份:2022
- 资助金额:
$ 42.35万 - 项目类别:
Transcription factor Mohawk in tendon and ligament degeneration and regeneration
转录因子莫霍克在肌腱和韧带退化和再生中的作用
- 批准号:
8722781 - 财政年份:2014
- 资助金额:
$ 42.35万 - 项目类别:
Transcription factor Mohawk in tendon and ligament degeneration and regeneration
转录因子莫霍克在肌腱和韧带退化和再生中的作用
- 批准号:
9064632 - 财政年份:2014
- 资助金额:
$ 42.35万 - 项目类别:
The Role of MicroRNA in Rheumatoid Arthritis Pathogenesis
MicroRNA 在类风湿关节炎发病机制中的作用
- 批准号:
7793402 - 财政年份:2009
- 资助金额:
$ 42.35万 - 项目类别:
The Role of MicroRNA in Rheumatoid Arthritis Pathogenesis
MicroRNA 在类风湿关节炎发病机制中的作用
- 批准号:
7587214 - 财政年份:2009
- 资助金额:
$ 42.35万 - 项目类别:
The role of microRNAs in chondrogenesis and arthritis
microRNA 在软骨形成和关节炎中的作用
- 批准号:
8265710 - 财政年份:2004
- 资助金额:
$ 42.35万 - 项目类别:
The role of microRNAs in chondrogenesis and arthritis
microRNA 在软骨形成和关节炎中的作用
- 批准号:
8471651 - 财政年份:2004
- 资助金额:
$ 42.35万 - 项目类别:
The role of microRNAs in cartilage homeostasis and osteoarthritis arthritis treatment
microRNA在软骨稳态和骨关节炎治疗中的作用
- 批准号:
10115614 - 财政年份:2004
- 资助金额:
$ 42.35万 - 项目类别:
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