Cell Senescence Regulating Osteoarthritis Progression: Sex-dependent Mechanisms
细胞衰老调节骨关节炎进展:性别依赖性机制
基本信息
- 批准号:10567551
- 负责人:
- 金额:$ 62.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-15 至 2027-11-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAgingAntiviral AgentsBone remodelingCartilageCell AgingCellsChondrocytesChronicClinicalCodeComplexDNA Transposable ElementsDataDegenerative polyarthritisDevelopmentDiseaseElderlyElementsFDA approvedFemaleFibrosisGenesGoalsHealthHumanInflammationInjuryInterleukin-1 betaInterventionJointsKnee OsteoarthritisKnowledgeLamivudineLengthLesionMedial meniscus structureMedicalMissionMolecularMusNuclearNucleosidesOutcomePathway interactionsPatientsPatternPharmaceutical PreparationsPhenotypePopulationPredispositionPrevalenceProcessPublic HealthRegulationRepressionResearchResistanceRetrotransposonReverse Transcriptase InhibitorsRoleSeveritiesSex DifferencesSignal TransductionSterilityStressTestingTranslatingTraumatic ArthropathyUnited States National Institutes of HealthWomanarticular cartilagecartilage degradationclinical practicederepressiondisabilitydisease disparitydrug developmentearly onseteffective therapyeffectiveness testinginnovationjoint destructionjoint injurymalemenmesenchymal stromal cellmouse modelnovel markernovel strategiesnucleoside inhibitorprecision medicinesenescencesextranscriptome sequencingtranscriptomics
项目摘要
Osteoarthritis (OA), a leading cause of disability in the elderly (aging OA), is a complex degenerative joint disease
involving articular cartilage degradation, chronic inflammation, and bone remodeling. In addition, joint injury can
trigger post-traumatic osteoarthritis (PTOA). The prevalence and severity of knee OA are higher in women than
men during aging, although female mice are more resistant to OA progression after injury. The scientific
challenge is the incomplete understanding of the sex-specific mechanisms regulating OA progression, which
hampers the development of disease-modifying osteoarthritis drugs that can target the process. The scientific
goal of this project is to determine the molecular mechanisms underlying sex-difference in OA progression. We
discovered that retrotransposon Long Interspersed Nuclear Element-1 (LINE-1, or L1), a novel marker of cell
senescence, is closely associated with OA lesions in both human and mice. Further, L1 activation mechanism
is sex dependent. Activation of stress-inducible miR-365 stimulates L1 and OA progression in female but not in
male during aging. Furthermore, senostatics that target cell senescence inhibit OA progression by inhibiting L1,
which is repressed in chondrocytes but de-repressed in senescent MSCs in the joint. These data suggest that
senescent MSCs can be a key target for effective treatment of OA. The innovative hypothesis is that females
are more susceptible to early-onset and progression of OA during aging because stress signals stimulate L1,
which leads to MSC senescence, SASP inflammation, and joint degeneration in female. On the other hand, after
OA onset is triggered by injury, males are more susceptible to OA progression because of the higher basal levels
of L1 and IL-1β in male. If so, intervention of aging-OA progression in female and PTOA progression in male can
be achieved by repressing L1 using FDA-approved anti-viral drug nucleoside reverse transcriptase inhibitor
(NRTI). This hypothesis will be tested through three aims. First, we will define activation patterns of L1 and cell
senescence in OA cartilage lesions of male and female patients. Second, we will determine sex-specific
mechanisms regulating OA progression in aging OA and PTOA using the sex-specific OA progression mouse
models. Third, we will develop sex-specific intervention for NRTIs to inhibit OA progression. This study has high
impact because it uncovers fundamental mechanisms of OA disease disparity between men and women. It is
innovative because it represents a new and distinct direction for the field by revealing sex-specific regulation of
OA progression through addressing a previously unsuspected role of retrotransposons in these processes. It
has significant clinical and translational values. If successful, NRTIs, which are safe and readily available, can
be re-purposed for OA treatment in human. It will not only change the concepts that drive the OA research field,
but also greatly impact the clinical practice of how we treat OA patients.
骨关节炎(OA)是一种复杂的退行性关节疾病,是老年人致残的主要原因
包括关节软骨退化、慢性炎症和骨重塑。此外,关节损伤可
引发创伤后骨关节炎(PTOA)。女性膝关节OA的患病率和严重程度高于男性,
尽管雌性小鼠在受伤后对OA进展的抵抗力更强。科学
挑战是对调节OA进展的性别特异性机制的不完全理解,
阻碍了针对这一过程的改善疾病的骨关节炎药物的开发。科学
本项目的目的是确定OA进展中性别差异的分子机制。我们
发现逆转录转座子长散布核元件-1(LINE-1,或L1),一种新的细胞标志物,
衰老与人和小鼠的OA病变密切相关。此外,L1激活机制
是依赖性的。应激诱导型miR-365的激活刺激女性L1和OA进展,但不刺激女性L1和OA进展。
男性在衰老过程中此外,靶向细胞衰老的衰老抑制剂通过抑制L1,
其在软骨细胞中被抑制,但在关节中衰老的MSC中去抑制。这些数据表明
衰老的MSC可以是有效治疗OA的关键靶标。创新的假设是,
在衰老过程中更容易受到OA的早发和进展的影响,因为压力信号刺激L1,
导致女性MSC衰老、SASP炎症和关节退变。另一方面,在
OA发作由损伤触发,由于基础水平较高,男性更容易发生OA进展
男性L1和IL-1β的表达。如果是这样的话,女性中的老化-OA进展和男性中的PTOA进展的干预可以
通过使用FDA批准的抗病毒药物核苷逆转录酶抑制剂抑制L1来实现
(NRTI)。这一假设将通过三个目标进行检验。首先,我们将定义L1和细胞的激活模式,
男性和女性患者OA软骨病变的衰老。其次,我们将确定性别特异性
使用性别特异性OA进展小鼠在老化OA和PTOA中调节OA进展的机制
模型第三,我们将针对NRTI制定针对性别的干预措施,以抑制OA进展。这项研究具有高度
影响,因为它揭示了男女之间OA疾病差异的基本机制。是
创新,因为它代表了一个新的和独特的方向,为该领域揭示性别特异性调节,
通过解决逆转录转座子在这些过程中的作用,OA进展。它
具有重要的临床和转化价值。如果成功的话,安全且容易获得的NRTI可以
重新用于人类OA治疗。它不仅将改变驱动OA研究领域的概念,
也极大地影响了我们如何治疗OA患者的临床实践。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
QIAN CHEN其他文献
QIAN CHEN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('QIAN CHEN', 18)}}的其他基金
Developing Nanopieces, a Platform RNAi Delivery Technology for Treatment of Multiple Diseases
开发 Nanopieces,一种用于治疗多种疾病的 RNAi 传递技术平台
- 批准号:
9777769 - 财政年份:2020
- 资助金额:
$ 62.14万 - 项目类别:
Repressing Retrotransposon LINE-1: New Concepts for Osteoarthritis Treatment
抑制逆转录转座子 LINE-1:骨关节炎治疗的新概念
- 批准号:
9912431 - 财政年份:2019
- 资助金额:
$ 62.14万 - 项目类别:
Repressing Retrotransposon LINE-1: New Concepts for Osteoarthritis Treatment
抑制逆转录转座子 LINE-1:骨关节炎治疗的新概念
- 批准号:
10019329 - 财政年份:2019
- 资助金额:
$ 62.14万 - 项目类别:
相似海外基金
Interplay between Aging and Tubulin Posttranslational Modifications
衰老与微管蛋白翻译后修饰之间的相互作用
- 批准号:
24K18114 - 财政年份:2024
- 资助金额:
$ 62.14万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
EMNANDI: Advanced Characterisation and Aging of Compostable Bioplastics for Automotive Applications
EMNANDI:汽车应用可堆肥生物塑料的高级表征和老化
- 批准号:
10089306 - 财政年份:2024
- 资助金额:
$ 62.14万 - 项目类别:
Collaborative R&D
The Canadian Brain Health and Cognitive Impairment in Aging Knowledge Mobilization Hub: Sharing Stories of Research
加拿大大脑健康和老龄化认知障碍知识动员中心:分享研究故事
- 批准号:
498288 - 财政年份:2024
- 资助金额:
$ 62.14万 - 项目类别:
Operating Grants
Baycrest Academy for Research and Education Summer Program in Aging (SPA): Strengthening research competencies, cultivating empathy, building interprofessional networks and skills, and fostering innovation among the next generation of healthcare workers t
Baycrest Academy for Research and Education Summer Program in Aging (SPA):加强研究能力,培养同理心,建立跨专业网络和技能,并促进下一代医疗保健工作者的创新
- 批准号:
498310 - 财政年份:2024
- 资助金额:
$ 62.14万 - 项目类别:
Operating Grants
関節リウマチ患者のSuccessful Agingに向けたフレイル予防対策の構築
类风湿性关节炎患者成功老龄化的衰弱预防措施的建立
- 批准号:
23K20339 - 财政年份:2024
- 资助金额:
$ 62.14万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Life course pathways in healthy aging and wellbeing
健康老龄化和福祉的生命历程路径
- 批准号:
2740736 - 财政年份:2024
- 资助金额:
$ 62.14万 - 项目类别:
Studentship
NSF PRFB FY 2023: Connecting physiological and cellular aging to individual quality in a long-lived free-living mammal.
NSF PRFB 2023 财年:将生理和细胞衰老与长寿自由生活哺乳动物的个体质量联系起来。
- 批准号:
2305890 - 财政年份:2024
- 资助金额:
$ 62.14万 - 项目类别:
Fellowship Award
I-Corps: Aging in Place with Artificial Intelligence-Powered Augmented Reality
I-Corps:利用人工智能驱动的增强现实实现原地老龄化
- 批准号:
2406592 - 财政年份:2024
- 资助金额:
$ 62.14万 - 项目类别:
Standard Grant
McGill-MOBILHUB: Mobilization Hub for Knowledge, Education, and Artificial Intelligence/Deep Learning on Brain Health and Cognitive Impairment in Aging.
McGill-MOBILHUB:脑健康和衰老认知障碍的知识、教育和人工智能/深度学习动员中心。
- 批准号:
498278 - 财政年份:2024
- 资助金额:
$ 62.14万 - 项目类别:
Operating Grants
Welfare Enhancing Fiscal and Monetary Policies for Aging Societies
促进老龄化社会福利的财政和货币政策
- 批准号:
24K04938 - 财政年份:2024
- 资助金额:
$ 62.14万 - 项目类别:
Grant-in-Aid for Scientific Research (C)