The Role of Cellular Senescence in Carpal Tunnel Syndrome

细胞衰老在腕管综合征中的作用

• 批准号: 10261518
• 负责人: Anne Gingery
• 金额: $ 67.07万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10261518
• 关键词: Address; Affect; Aging; American; Animal Model; Apoptosis; Appearance; Attenuated; Automobile Driving; Biology; Biopsy; CD47 gene; CDKN2A gene; Carpal Tunnel Syndrome; Cell Aging; Cell Transplantation; Cell model; Cells; Chronic; Connective Tissue; Connective Tissue Cells; Dasatinib; Data; Diabetes Mellitus; Disease; Disease Progression; Etiology; Exhibits; Failure; Fibroblasts; Fibrosis; Geroscience; Hormonal Change; Human; Immune Evasion; In Vitro; Interferon Type II; Intervention; Metabolic; Modeling; Molecular; National Institute of Neurological Disorders and Stroke; Obesity; Operative Surgical Procedures; Oryctolagus cuniculus; PDGFA gene; Pathologic; Pathology; Pathway interactions; Patients; Persons; Phenotype; Plasminogen Activator Inhibitor 1; Play; Prevalence; Prevention; Process; Quality of life; Quercetin; Resistance; Resolution; Risk Factors; Role; Severities; TP53 gene; Testing; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Translating; Transplantation; Work; age related; beta-Galactosidase; cellular targeting; comorbidity; cost; cost estimate; design; disease mechanisms study; disease phenotype; effective therapy; efficacy evaluation; experimental study; in vivo; innovation; lost work time; median nerve; middle age; new therapeutic target; novel; novel therapeutic intervention; pathological aging; pharmacologic; programmed cell death ligand 1; response; senescence; therapeutic target; tissue culture; transplant model; wound healing

Project Summary/Abstract Carpal Tunnel Syndrome (CTS) is an idiopathic, non-inflammatory, age-related fibrotic disorder resulting in compression of the median nerve that affects 10 million Americans annually. Despite the prevalence, cost, and societal impact of CTS, little progress in its treatment and prevention has been made in the past 50 years, primarily due to the lack of mechanistic understanding of disease etiology. Aging is a major risk factor not only for CTS, but also for fibrosis and cellular senescence. Senescent cells exhibit a senescence-associated secretory phenotype (SASP) that is important for wound healing; however, failure to limit this response appropriately leads to fibrotic disease phenotypes. Our preliminary data shows that markers of cellular senescence, including senescence associated β-galactosidase, p16Ink4a, p53; immune evasion markers, as well as SASP factors are increased in both the tissue and cells of the subsynovial connective tissue (SSCT) of CTS patients. Further we have found that type II interferon ɣ (IFNɣ) is expressed in the SASP, and that it induces immune evasion markers. Moreover, targeting senescent pathways in human SSCT cultures using the senolytics dasatinib + quercetin reduces markers of senescence and fibrosis. Thus, our central hypothesis is that senescent cell accumulation in the SSCT is causally implicated in pathological aging and fibrosis found in CTS and that elimination of these senescent cells in the SSCT will attenuate the progression of this pathological fibrosis and thus alleviate disease progression. Importantly, we have developed a rabbit model of CTS and progressive SSCT fibrosis that will allow us to study disease mechanisms in vivo. Therefore, to test this hypothesis, we propose the following specific aims: 1) elucidate the mechanism by which IFNɣ promotes senescence and immune evasion in the SSCT, 2) determine the contribution of senescence to fibrosis in CTS, and 3) evaluate senolytic therapy in vivo. This work will significantly and fundamentally advance our understanding of SSCT fibrosis in CTS, which is a disease of aging and is associated with multiple age-related metabolic co-morbidities. Our discovery of increased senescent fibroblast expression of type IFNɣ in fibrotic tissue and cells could provide a novel therapeutic target for resolution of tissue fibrosis. The innovative aspects of this project are: it will critically test the heretofore untested hypothesis that senescent cells promote CTS, address fundamental questions about disease-related senescent cells, test the novel hypothesis that targeting senescence cells will be a novel therapeutic strategy for CTS and for the first time explore the role of IFNɣ on CTS pathology. This work aligns well with the “Geroscience Hypothesis” which postulates that interventions that slow the aging process will simultaneously delay the appearance or severity of many chronic age-related diseases. CTS is associated with multiple co-morbidities and thus, in addition to advancing the field of aging and fibrosis biology, novel targeted strategies for CTS treatment and prevention derived from these studies could rapidly be translated into new, non-surgical therapies for the millions of people who suffer with CTS.

项目总结/摘要 腕管综合征（CTS）是一种特发性、非炎症性、年龄相关性纤维化疾病， 正中神经受压每年影响一千万美国人尽管流行，成本， CTS的社会影响，在过去的50年里，其治疗和预防进展甚微， 主要是由于缺乏对疾病病因学的机械理解。老龄化是一个主要的风险因素，不仅 对于CTS，也对于纤维化和细胞衰老。衰老细胞表现出衰老相关的 分泌表型（SASP），对伤口愈合很重要;然而，未能限制这种反应 适当地导致纤维化疾病表型。我们的初步数据显示， 衰老，包括衰老相关的β-半乳糖苷酶、p16 Ink 4a、p53;免疫逃避标志物，以及 由于SASP因子在CTS的滑膜下结缔组织（SSCT）的组织和细胞中均增加， 患者此外，我们还发现，II型干扰素β（IFN β）在SASP中表达，并且它诱导 免疫逃避标记。此外，在人SSCT培养物中，使用 senolytics达沙替尼+槲皮素减少衰老和纤维化的标志物。因此，我们的中心假设是 SSCT中的衰老细胞积累与病理性衰老和纤维化有因果关系， CTS和在SSCT中消除这些衰老细胞将减弱这种进展。 病理性纤维化，从而减轻疾病进展。重要的是，我们已经开发了一种兔子模型， CTS和进行性SSCT纤维化，这将使我们能够在体内研究疾病机制。因此，为了测试 基于这一假设，我们提出了以下具体目标：1）阐明IFN γ促进 SSCT中的衰老和免疫逃避，2）确定CTS中衰老对纤维化的贡献， 和3）评估体内衰老清除疗法。这项工作将从根本上大大推动我们的 理解CTS中的SSCT纤维化，这是一种衰老疾病，与多种年龄相关的疾病有关。 代谢合并症。我们发现纤维化中衰老成纤维细胞IFN γ表达增加 组织和细胞可以为组织纤维化的解决提供新的治疗靶点。各个创新方面 该项目的主要目的是：它将严格检验迄今为止尚未检验的假设，即衰老细胞促进CTS， 解决与疾病相关的衰老细胞的基本问题，测试新的假设， 衰老细胞将是CTS的一种新的治疗策略，并首次探索IFN γ的作用。 CTS病理学。这项工作与“老年科学假说”很好地吻合，该假说假定干预措施 减缓衰老过程的药物将同时延缓许多与年龄相关的慢性疾病的出现或严重程度 疾病CTS与多种合并症有关，因此，除了推进衰老领域外， 和纤维化生物学，从这些研究中获得的CTS治疗和预防的新靶向策略 可以迅速转化为新的非手术疗法，用于数百万患有CTS的人。