The Role of Cellular Senescence in Carpal Tunnel Syndrome

项目摘要/摘要 腕管综合征(CTS)是一种特发性、非炎症性、与年龄相关的纤维化疾病，导致 每年影响1000万美国人的正中神经压迫。尽管流行、成本和 尽管CTS的社会影响不大，但在过去50年中，其治疗和预防方面进展甚微， 主要是由于缺乏对疾病病因学的机械性理解。老龄化不仅是一个主要的风险因素 对于CTS，但也对纤维化和细胞衰老。衰老的细胞表现出与衰老相关的 对伤口愈合很重要的分泌表型(SASP)；然而，未能限制这种反应 适当地导致纤维化疾病的表型。我们的初步数据显示，细胞标志物 衰老，包括衰老相关的β-半乳糖苷酶、p16INK4a、p53；免疫逃避标记物 随着SASP因子在CTS滑膜下结缔组织(SSCT)的组织和细胞中的表达增加 病人。此外，我们还发现II型干扰素ɣ(干扰素ɣ)在SASP中表达，并诱导 免疫逃避标记。此外，针对人类SSCT培养中的衰老途径，使用 抗衰老药物达沙替尼+槲皮素可减少衰老和纤维化的标记物。因此，我们的中心假设是 SSCT中衰老细胞的堆积与病理性衰老和纤维化有关 CTS和消除SSCT中这些衰老细胞将延缓这种进展 病理性纤维化，从而延缓疾病进展。重要的是，我们开发了一种兔模型 CTS和进行性SSCT纤维化，这将使我们能够研究体内的疾病机制。因此，为了测试 在这一假设下，我们提出了以下具体目标：1)阐明干扰素ɣ促进 SSCT中的衰老和免疫逃避，2)决定衰老对CTS纤维化的贡献， (3)体内感觉神经溶解治疗评价。这项工作将显著地从根本上推动我们的 对CTS中SSCT纤维化的认识，CTS是一种增龄性疾病，与多种年龄相关 代谢合并症。肝纤维化患者衰老成纤维细胞干扰素ɣ表达增加的研究 组织和细胞可为解决组织纤维化提供新的治疗靶点。创新方面 该项目的特点是：它将批判性地检验迄今为止未经检验的假设，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，测试靶向 衰老细胞将成为CTS的一种新的治疗策略，并首次探讨干扰素ɣ在 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 延缓衰老进程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与多种并存疾病有关，因此，除了促进老龄化领域 和纤维化生物学，从这些研究中衍生出治疗和预防CTS的新的靶向策略 可以迅速转化为新的非手术疗法，适用于数百万患有CTS的患者。

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.