The Role of Cellular Senescence in Carpal Tunnel Syndrome
细胞衰老在腕管综合征中的作用
基本信息
- 批准号:10261518
- 负责人:
- 金额:$ 67.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAffectAgingAmericanAnimal ModelApoptosisAppearanceAttenuatedAutomobile DrivingBiologyBiopsyCD47 geneCDKN2A geneCarpal Tunnel SyndromeCell AgingCell TransplantationCell modelCellsChronicConnective TissueConnective Tissue CellsDasatinibDataDiabetes MellitusDiseaseDisease ProgressionEtiologyExhibitsFailureFibroblastsFibrosisGeroscienceHormonal ChangeHumanImmune EvasionIn VitroInterferon Type IIInterventionMetabolicModelingMolecularNational Institute of Neurological Disorders and StrokeObesityOperative Surgical ProceduresOryctolagus cuniculusPDGFA genePathologicPathologyPathway interactionsPatientsPersonsPhenotypePlasminogen Activator Inhibitor 1PlayPrevalencePreventionProcessQuality of lifeQuercetinResistanceResolutionRisk FactorsRoleSeveritiesTP53 geneTestingTherapeuticTimeTissuesTransforming Growth Factor betaTranslatingTransplantationWorkage relatedbeta-Galactosidasecellular targetingcomorbiditycostcost estimatedesigndisease mechanisms studydisease phenotypeeffective therapyefficacy evaluationexperimental studyin vivoinnovationlost work timemedian nervemiddle agenew therapeutic targetnovelnovel therapeutic interventionpathological agingpharmacologicprogrammed cell death ligand 1responsesenescencetherapeutic targettissue culturetransplant modelwound healing
项目摘要
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
项目成果
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Anne Gingery的其他文献
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{{ truncateString('Anne Gingery', 18)}}的其他基金
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:
10655902 - 财政年份:2020
- 资助金额:
$ 67.07万 - 项目类别:
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