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.
骨关节炎是导致老年人残疾的主要原因之一,是一种复杂的退行性关节疾病
涉及关节软骨退化、慢性炎症和骨重建。此外,关节损伤可能
引发创伤后骨关节炎(PTOA)。女性膝关节骨性关节炎的患病率和严重程度高于
雄性小鼠在衰老过程中,尽管雌性小鼠在损伤后对OA进展更具抵抗力。科学的
挑战是对调节骨性关节炎进展的特定性别机制的不完全理解,这
阻碍了可以针对这一过程的疾病修改骨性关节炎药物的开发。科学的
该项目的目标是确定在骨性关节炎进展过程中存在性别差异的分子机制。我们
发现反转录转座子长穿插核元件-1(LINE-1,或L1),这是一种新的细胞标记
衰老与人类和小鼠的骨性关节炎病变密切相关。此外,L1激活机制
是性依赖的。应激诱导的miR-365激活可刺激女性L1和OA进展,但不能
男性在衰老过程中。此外,靶细胞衰老的抗衰老药物通过抑制L1来抑制OA的进展,
它在软骨细胞中被抑制,但在关节中衰老的MSCs中被解除抑制。这些数据表明
衰老的骨髓间充质干细胞可以成为有效治疗骨性关节炎的关键靶点。创新的假设是女性
在衰老过程中更容易发生早发性和进行性骨性关节炎,因为应激信号刺激L1,
这会导致女性MSC衰老、SASP炎症和关节退变。另一方面,在
骨性关节炎的发病是由损伤引发的,男性由于基础水平较高而更容易发生骨性关节炎的进展
男性L1和IL-1β的表达。如果是这样的话,干预女性的衰老-OA进展和男性的PTOA进展可以
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
男性和女性患者骨性关节炎软骨病变的衰老。第二,我们将确定具体的性别
利用性别特异性的骨性关节炎进展小鼠调节老年性骨性关节炎和PTOA的骨性关节炎进展的机制
模特们。第三,我们将为NRTI开发针对性别的干预措施,以抑制OA的进展。这项研究具有很高的
影响,因为它揭示了男女之间骨性关节炎疾病差异的基本机制。它是
创新,因为它代表了该领域的一个新的和独特的方向,揭示了针对性别的监管
通过解决反转录转座子在这些过程中以前未被怀疑的作用来实现OA的进展。它
具有重要的临床和翻译价值。如果成功,安全和容易获得的非传染性药物可以
被重新用于治疗人类的骨性关节炎。它不仅将改变推动办公自动化研究领域的概念,
而且也极大地影响了我们临床治疗骨性关节炎患者的方式。
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
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
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
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)