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.

项目概要/摘要 腕管综合症 (CTS) 是一种特发性、非炎症性、与年龄相关的纤维化疾病，导致 正中神经受压每年影响 1000 万美国人，尽管其患病率、费用和成本都很高。 CTS 的社会影响，过去 50 年来其治疗和预防方面几乎没有取得任何进展， 衰老不仅是一个主要风险因素 用于 CTS，还用于纤维化和细胞衰老 衰老细胞表现出衰老相关性。 分泌表型（SASP）对伤口愈合很重要，但未能限制这种反应； 我们的初步数据表明，细胞标记物适当地导致纤维化疾病表型。 衰老，包括衰老相关的 β-半乳糖苷酶、p16Ink4a、p53 以及免疫逃避标记物； 因为 CTS 滑膜下结缔组织 (SSCT) 的组织和细胞中的 SASP 因子均增加 此外，我们还发现 II 型干扰素 ɣ (IFNɣ) 在 SASP 中表达，并且它诱导 此外，利用人类 SSCT 培养物中的衰老途径。 senolytics 达沙替尼 + 槲皮素可减少衰老和纤维化的标志物因此，我们的中心假设是。 SSCT 中衰老细胞的积累与病理性衰老和纤维化有关 CTS 和 SSCT 中消除这些衰老细胞将减弱这种情况的进展 重要的是，我们开发了一种兔模型。 CTS 和进行性 SSCT 纤维化将使我们能够在体内研究疾病机制，从而进行测试。 针对这一假设，我们提出以下具体目标：1）阐明IFNɣ促进的机制 SSCT 中的衰老和免疫逃避，2) 确定衰老对 CTS 中纤维化的贡献， 3）评估体内的 senolytic 疗法。这项工作将从根本上显着地推进我们的研究。 了解 CTS 中的 SSCT 纤维化，CTS 是一种衰老疾病，与多种年龄相关的疾病有关 我们发现纤维化中 IFNɣ 型衰老成纤维细胞表达增加。 组织和细胞可以为解决组织纤维化提供新的治疗靶点。 该项目的主要内容是：它将严格检验迄今为止未经检验的假设，即衰老细胞促进 CTS， 解决有关疾病相关衰老细胞的基本问题，测试靶向的新假设 衰老细胞将成为 CTS 的一种新型治疗策略，并首次探索 IFNɣ 对 CTS 的作用 CTS 病理学与“老年科学假说”非常吻合，该假说假设干预措施。 减缓衰老过程将同时延迟许多与年龄相关的慢性疾病的出现或严重程度 CTS 与多种并发症相关，因此除了促进衰老领域的发展之外。 和纤维化生物学，源自这些研究的 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，治疗数百万 CTS 患者。