Sirtuins in Lung Aging and Fibrosis
Sirtuins 在肺衰老和纤维化中的作用
基本信息
- 批准号:9210543
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-01-01 至 2019-12-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAcetylationAffectAgeAgingAnimalsApoptosisApplications GrantsBioenergeticsBiologicalBleomycinBlood VesselsCell AgingCellsCicatrixClinicalCollagenDNA MethylationDataDevelopmentDiagnosisDiseaseDown-RegulationEnzymesEpigenetic ProcessEquilibriumFibroblastsFibrosisGasesGenesGeneticHamman-Rich syndromeHeartHumanImmunohistochemistryIncidenceKidneyKnock-outLaboratoriesLinkLiverLungLung diseasesMaintenanceMediatingMesenchymalMitochondriaMitochondrial ProteinsModelingMolecularMorbidity - disease rateMusMyofibroblastNADPH OxidaseOxidation-ReductionPathogenesisPharmaceutical PreparationsPhasePhenotypePirfenidonePopulationPrevalencePulmonary FibrosisReactive Oxygen SpeciesResistanceResolutionRespiratory FailureRoleSignal TransductionSirtuinsStructure of parenchyma of lungSurvival RateTestingTimeTissuesUnited StatesUnited States Department of Veterans Affairsage relatedagedbody systemburden of illnessclinical efficacyfibrogenesishistone modificationhuman subjectimprovedin vivoinsightlung injurymitochondrial dysfunctionmortalitymouse modelnovelnovel therapeutic interventionnovel therapeuticsolder patientpublic health relevanceresponsesenescence
项目摘要
DESCRIPTION (provided by applicant)
Idiopathic pulmonary fibrosis (IPF) is a disease of aging. IPF carries a high morbidity and mortality, with a median survival rate of less than three years. The incidence and prevalence of IPF increase drastically with age; however, despite this strong association, cellular/molecular mechanisms that account for the aging predilection to fibrotic disease have not been elucidated. Recent studies from our laboratory have identified a reactive oxygen species (ROS)-generating enzyme, NADPH oxidase-4 (Nox4), in mediating differentiation of fibroblasts (Fbs) to myofibroblasts (MFbs), key effectors of fibrogenesis, and in in-vivo lung fibrosis in murine models of lung injury. Our preliminary studies indicate that the biological actions of Nox4 may be modulated by the expression of SIRT3, a mitochondrial sirtuin. Both cellular senescence and TGF-β1 mediate suppression of SIRT3; our preliminary studies support a role for epigenetic silencing of SIRT3 involving both DNA methylation and histone modification. Decreased expression of SIRT3 promotes a senescent and pro-fibrotic Fb phenotype. TGF-β1-induced down-regulation of SIRT3 is associated with hyper-acetylation of mitochondrial proteins, supporting a role for altered mitochondrial bioenergetics in MFbs. Human subjects with IPF express low levels of SIRT3 in myofibroblastic foci (by immunohistochemistry), as well as in ex-vivo Fbs isolated from IPF lungs. We have developed a novel aging model of non-resolving fibrosis in mice; fibrosis in young mice (2 months) resolves by >50% by 4 months post-bleomycin, whereas aged mice (18 months) show persistent fibrotic response. While SIRT3 levels decrease during the fibrogenic phase in both groups, young mice demonstrate a capacity to recover SIRT3 levels during resolution; in contrast, aged mice manifest sustained down-regulation of SIRT3. The central hypothesis to be tested in this grant proposal is that, in the context of aging, lung injury results in sustained, epigenetically-regulated SIRT3 silencing that leads to mitochondrial dysfunction, MFb senescence and apoptosis resistance, leading to persistent fibrosis with aging. Our specific aims are to: (1) determine epigenetic mechanisms for SIRT3 down-regulation with cellular senescence and with TGF-β1 signaling in lung Fbs; (2) determine the role of SIRT3 in regulating mitochondrial bioenergetics, Fb senescence and apoptosis resistance; (3) determine whether whole-animal SIRT3 knockout and/or conditional genetic deletion of SIRT3 in collagen-producing/mesenchymal cells induce(s) persistent fibrosis in young mice. The completion of the Aims in this proposal will: (a) elucidate epigenetic mechanisms that control SIRT3 expression with cellular senescence/aging; (b) provide mechanistic insights into the role of SIRT3 in maintenance of mitochondrial bioenergetics and cellular plasticity/fate; (c) provide proof-of-concept that SIRT3 induction in the context of age-associated fibrosis facilitates fibrosis resolution, uncovering a novel therapeutic approach to non-resolving fibrotic disorders such as IPF.
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Victor J. Thannickal其他文献
Long noncoding RNA Malat1 regulates differential activation of macrophage and response to lung injury
长非编码 RNA Malat1 调节巨噬细胞的差异激活和对肺损伤的反应
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:8
- 作者:
Huachun Cui;Sami Banerjee;Sijia Guo;Na Xie;Jing Ge;Dingyuan Jiang;Martin Zörnig;Victor J. Thannickal;Gang Liu - 通讯作者:
Gang Liu
Victor J. Thannickal的其他文献
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{{ truncateString('Victor J. Thannickal', 18)}}的其他基金
AMPK in the Development and Resolution of Lung Fibrosis
AMPK 在肺纤维化的发展和解决中的作用
- 批准号:
10320917 - 财政年份:2019
- 资助金额:
-- - 项目类别:
AMPK in the Development and Resolution of Lung Fibrosis
AMPK 在肺纤维化的发展和解决中的作用
- 批准号:
10083647 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Therapeutic Targeting of the Myofibroblast in Fibrotic Lung Disease
纤维化肺病中肌成纤维细胞的治疗靶向
- 批准号:
10218247 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Therapeutic Targeting of the Myofibroblast in Fibrotic Lung Disease
纤维化肺病中肌成纤维细胞的治疗靶向
- 批准号:
9980973 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Therapeutic Targeting of the Myofibroblast in Fibrotic Lung Disease
纤维化肺病中肌成纤维细胞的治疗靶向
- 批准号:
8735177 - 财政年份:2013
- 资助金额:
-- - 项目类别:
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