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/文摘