EGFR signaling in osteoarthritis and treatment
骨关节炎中的 EGFR 信号传导及其治疗
基本信息
- 批准号:10701673
- 负责人:
- 金额:$ 44.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-30 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AdultAge YearsAgingAnimal ModelAnimalsArthralgiaAttenuatedBiologyBovine CartilageCREB1 geneCartilageCellsChondrocytesDTR geneDataDegenerative polyarthritisDevelopmentDiseaseElderlyEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorGefitinibGeneral PopulationGenesGrowth FactorHealthHistologyHomeostasisHypertrophyJointsKneeKnee OsteoarthritisKnowledgeLifeLigandsLubricationMechanicsMediatingModelingMolecularMusOperative Surgical ProceduresPainPathogenesisPathway interactionsPenetrationPersonal SatisfactionPharmaceutical PreparationsPharmacotherapyPhenotypePrevalenceProteoglycanReceptor Protein-Tyrosine KinasesReceptor SignalingRegulationResolutionRoleSclerosisSeriesSignal PathwaySomatotropinStructureSurfaceTestingTherapeutic EffectTransforming Growth Factor alphaTranslatingage relatedaggrecanarthropathiesarticular cartilagebehavior testcartilage degradationclinically relevantdesigndisabilityexperimental studygain of functiongenetic approachgenetic manipulationimprovedknock-downloss of functionmechanical propertiesmouse modelnanoparticlenovelnovel therapeutic interventionoverexpressionpreventrepairedresponsesubchondral bone
项目摘要
Project Summary
Osteoarthritis (OA) is a classic age-related disorder and the most common cause ofpain and disability in
the
elderly.
It is primarily characterized by the progressive destruction of articular cartilage. This past decade
has witnessed significant advances in deciphering the basic mechanisms by which OA develops. However, to
date, no disease modifying drug therapy is available for preventing OA development and repairing the
degenerative cartilage. The uppermost superficial zone of articular cartilage is the first line of defense against
OA initiation. We recently found that epidermal growth factor receptor (EGFR), a tyrosine kinase receptor, is
expressed abundantly throughout the articular cartilage with its active form (p-EGFR) predominantly located in
the superficial zone. Interestingly, at the onset of OA, p-EGFR amount, along with two major EGFR ligands
(TGFα and HBEGF), were markedly attenuated while the amount of Mig6, a negative inhibitor of EGFR, was
enhanced, suggesting a potential role for EGFR signaling pathway in cartilage homeostasis and diseases.
Using a series of mouse models with deficient or overactivated EGFR activity by genetic manipulation of Egfr
and Mig6 genes, we and others have demonstrated that EGFR signaling is critical for maintaining the number
and mechanical properties of superficial chondrocytes, suppressing their hypertrophy, promoting proteoglycan
4 (Prg4) expression, and stimulating surface lubrication function. Most strikingly, in aging- and surgery-induced
OA models, mice with chondrocyte-specific (Col2-Cre) EGFR deficiency developed the most severe OA
phenotypes, including a complete loss of articular cartilage, subchondral bone sclerosis, and escalated joint
pain. Hence, we hypothesize that EGFR signaling is essential for maintaining the structure and function of the
superficial layer in the articular cartilage and thus, can be targeted for OA treatment. Our objectives are to
understand the role of this novel signaling pathway in articular cartilage homeostasis and diseases, and to
seek approaches targeting this pathway for OA treatment. To achieve these, we will perform the following
aims: 1) determine the temporal role of EGFR signaling in OA pathogenesis; 2) elucidate the mechanisms of
the protective action of EGFR on articular cartilage; 3) investigate whether EGFR signaling is a promising
target for OA treatment. Complementary genetic approaches, such as EGFR vs Mig6, loss of function vs gain
of function, and aggrecan-CreER vs Prg4-CreER, will be used throughout the proposal. Moreover, we have
designed and synthesized TGFα-conjugated nanoparticles with prolonged retention and penetration abilities in
knee cartilage. A proof-of-principal experiment will be performed to examine its therapeutic effects on cartilage
degeneration at different OA stages. This proposal will uncover critical EGFR actions in knee articular cartilage
and provide crucial evidence for targeting this novel pathway in OA therapies. Once successfully
accomplished, this project could be quickly translated into large animal OA models followed by clinically
relevant applications that would eventually improve the health and well-being of the general public.
项目摘要
骨关节炎是一种典型的与年龄相关的疾病,也是导致疼痛和残疾的最常见原因
这个
老年人。
其主要特征是关节软骨的进行性破坏。过去的十年
在破译开放式获取发展的基本机制方面取得了重大进展。然而,为了
到目前为止,还没有疾病修饰药物疗法可用于预防骨性关节炎的发展和修复
退变的软骨。关节软骨最上面的表面区是抵御
办公自动化入门。我们最近发现,表皮生长因子受体(EGFR),一种酪氨酸激酶受体,是一种
在关节软骨中大量表达,其活性形式(p-EGFR)主要位于
表面区。有趣的是,在OA开始时,p-EGFR与两个主要的EGFR配体一起
(转化生长因子α和血管内皮细胞生长因子)的表达明显减弱,而表皮生长因子受体的负向抑制因子Mig6的量则明显减少。
增强,提示EGFR信号通路在软骨内稳态和疾病中可能发挥作用。
利用EGFR基因操作建立一系列EGFR活性低下或过度激活的小鼠模型
和Mig6基因,我们和其他人已经证明了EGFR信号对维持这一数量至关重要
和浅层软骨细胞的机械性能,抑制其肥大,促进蛋白多糖
4(Prg4)的表达,并具有刺激表面润滑作用。最引人注目的是,在衰老和手术诱导的
在骨性关节炎模型中,软骨细胞特异性(COL2-CRE)EGFR缺乏的小鼠发生最严重的骨性关节炎
表型,包括关节软骨完全丧失,软骨下骨硬化和关节升级
疼痛。因此,我们假设EGFR信号对维持细胞的结构和功能是必不可少的。
关节软骨中的浅层,因此,可以作为治疗OA的靶点。我们的目标是
了解这一新的信号通路在关节软骨内稳态和疾病中的作用,并
寻找针对这一途径的治疗OA的方法。为了实现这些目标,我们将执行以下操作
目的:1)确定EGFR信号在骨性关节炎发病机制中的时间作用;2)阐明骨性关节炎的发病机制
EGFR对关节软骨的保护作用;3)研究EGFR信号转导是否有前景
骨性关节炎治疗的靶点。互补遗传方法,如EGFR与Mig6、功能丧失与获得
功能,以及aggrecan-Creer与Prg4-Creer,将在整个提案中使用。此外,我们有
设计合成具有长时间滞留和穿透能力的转化生长因子α偶联纳米粒
膝关节软骨。将进行一项主要实验,以检验其对软骨的治疗效果。
退行性变在不同的骨性关节炎阶段。这项提案将揭示膝关节软骨中关键的EGFR作用。
并为在骨性关节炎治疗中靶向这一新途径提供了重要证据。一旦成功
该项目完成后,可以迅速转化为大型动物骨性关节炎模型,随后在临床上
相关应用,最终将改善公众的健康和福祉。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Ling Qin', 18)}}的其他基金
Control of bone physiology by a novel type of adipose cells
新型脂肪细胞对骨生理学的控制
- 批准号:
10405549 - 财政年份:2021
- 资助金额:
$ 44.28万 - 项目类别:
Control of bone physiology by a novel type of adipose cells
新型脂肪细胞对骨生理学的控制
- 批准号:
10577829 - 财政年份:2021
- 资助金额:
$ 44.28万 - 项目类别:
Fat and synovial tissue remodeling in joint osteoarthritis
关节骨关节炎中的脂肪和滑膜组织重塑
- 批准号:
10308923 - 财政年份:2021
- 资助金额:
$ 44.28万 - 项目类别:
EGFR signaling in osteoarthritis and treatment
骨关节炎中的 EGFR 信号传导及其治疗
- 批准号:
10417220 - 财政年份:2020
- 资助金额:
$ 44.28万 - 项目类别:
EGFR signaling in osteoarthritis and treatment
骨关节炎中的 EGFR 信号传导及其治疗
- 批准号:
10266828 - 财政年份:2020
- 资助金额:
$ 44.28万 - 项目类别:
Dissecting the heterogeneity of bone marrow mesenchymal lineage progenitors
剖析骨髓间充质谱系祖细胞的异质性
- 批准号:
9883719 - 财政年份:2019
- 资助金额:
$ 44.28万 - 项目类别:
Mechanism of radiotherapy-induced osteoporosis and its treatment
放疗引起骨质疏松的机制及治疗
- 批准号:
8964347 - 财政年份:2015
- 资助金额:
$ 44.28万 - 项目类别:
Mechanism of radiotherapy-induced osteoporosis and its treatment
放疗引起骨质疏松的机制及治疗
- 批准号:
9322618 - 财政年份:2015
- 资助金额:
$ 44.28万 - 项目类别:
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