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:10610127
- 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 2025-09-30
- 项目状态:未结题
- 来源:
- 关键词:AccountingAffectAgeAgingAlveolar MacrophagesApoptosisApplications GrantsAwardBinding ProteinsBioenergeticsBleomycinBlood VesselsCREBBP geneCell AgingCicatrixClinicalComplementary DNAConstitutionCyclic AMP-Responsive DNA-Binding ProteinDataDevelopmentDiseaseDown-RegulationEP300 geneEpigenetic ProcessEventFibroblastsFibrosisGasesGeneticHeartHumanImmunohistochemistryImpairmentIncidenceKidneyLeadLiverLungLung diseasesMediatingMitochondriaModelingMolecularMorbidity - disease rateMusNuclearParacrine CommunicationPatientsPharmaceutical PreparationsPharmacologyPhasePhenotypePirfenidonePlasmidsPopulationPredispositionPrevalencePulmonary FibrosisRecoveryRegulationResistanceResolutionRespiratory FailureRisk FactorsRoleSignal PathwaySignal TransductionSirtuinsStructure of parenchyma of lungSurvival RateTestingTimeTissuesTransforming Growth FactorsUnited StatesUnited States Department of Veterans Affairsagedbody systemburden of illnessclinical efficacydisabling diseaseepigenetic regulationfibrotic lungfibrotic lung diseasehuman subjectidiopathic pulmonary fibrosisimprovedin vivoinjury and repairinsightlung injurymacrophagemitochondrial dysfunctionmortalitynintedanibnovel therapeutic interventionnovel therapeuticsolder patientparacrinepatient populationprofibrotic cytokineprotective effectreconstitutionsenescencetranscription factor
项目摘要
Human fibrotic disorders affect many organ systems including heart, blood vessels, kidney, liver and lung,
accounting for excessive disease burden in the U.S., including among our Veterans Administration (VA) patient
population. The most common fibrotic lung disease, idiopathic pulmonary fibrosis (IPF), is characterized by
excessive scar tissue formation and irreversible destruction of the lung parenchyma, resulting in gas-exchange
abnormalities and ultimately respiratory failure. Aging is strongest risk factor for IPF; however, the
cellular/molecular mechanisms that account for the age-associated predilection to fibrotic disease are only
beginning to be explored. Improved understanding of the role of aging in this disease will aid in the
development of novel therapies with greater clinical efficacy.
In support of this VA Merit Award renewal application, we have made several recent contributions to our
understanding of aging mechanisms in lung injury and repair mechanisms. Human subjects with IPF express
low levels of the mitochondrial sirtuin, SIRT3, in myofibroblastic foci and in ex-vivo fibroblasts isolated from IPF
lungs. This down-regulation of SIRT3 is replicated in an aging model of non-resolving fibrosis in mice; while
fibrosis in young mice largely resolves over 2-4 months post-bleomycin, aged mice manifest persistent fibrosis.
Our data indicate that this capacity for fibrosis resolution in young mice is associated with recovery of SIRT3
levels in the late reparative phase of lung injury, while this is absent in aged mice. However, re-constitution of
SIRT3 (via lung-targeted non-viral cDNA plasmid delivery) restores the capacity for fibrosis resolution in aged
mice. This protective effect is associated with in-vivo activation of FoxO3a, evidenced by higher levels of
nuclear FoxO3a. Both cellular senescence and the pro-fibrotic cytokine, transforming growth factor-β1 (TGF-
β1) induce a down-regulation of SIRT3 and FoxO3a, events that lead to mitochondrial dysfunction,
senescence and apoptosis resistance of lung fibroblasts. Our studies also support the possibility that
modulation of SIRT3 in alveolar macrophages regulates fibroblast activation of FoxO3a by a paracrine
mechanism. Additionally, the histone acetyltransferases, p300 and cyclic AMP-response element binding
protein (CREB)-binding protein (CBP), are implicated in the epigenetic down-regulation of SIRT3 by TGF-β1
and cellular senescence. Impaired activation of the SIRT3-FoxO3a signaling axis promotes a senescent and
apoptosis-resistant fibroblast phenotype, which drives persistent/non-resolving fibrosis.
The central hypothesis to be tested in this grant proposal is that persistent/non-resolving fibrosis
associated with aging is mediated by impaired activation of Foxo3a in fibroblasts, either by SIRT3 deficiency in
fibroblasts themselves or by macrophage-derived paracrine mechanisms, contributes to mitochondrial
dysfunction, senescence and apoptosis resistance of lung fibroblasts.
Our specific aims are to: (1) elucidate p300/CBP-dependent epigenetic regulation of SIRT3 in lung
fibroblasts and alveolar macrophages that mediate pro-resolution phenotypes; (2) investigate the role of the
SIRT3-FoxO3a signaling axis in restoring mitochondrial bioenergetics and apoptosis susceptibility to
senescent/fibrotic lung fibroblasts; and (3) determine whether reconstitution of SIRT3 by
genetic/pharmacologic approaches promotes fibrosis resolution in aged mice via the activation of FoxO3a in
lung fibroblasts. The completion of the Aims in this proposal will: (a) uncover epigenetic mechanisms that
control SIRT3 expression with cellular senescence/aging; (b) provide mechanistic insights into the role of
SIRT3-FoxO3a signaling in the regulation of mitochondrial bioenergetics and cellular plasticity/fate; and (c)
elucidate macrophage-fibroblast crosstalk and SIRT3 regulation of pro-resolving macrophages; and (d) provide
proof-of-concept that activation of the SIRT3-FoxO3a signaling pathway promotes fibrosis resolution, leading
to new therapeutic approaches for progressive lung diseases.
人体纤维化疾病影响许多器官系统,包括心脏、血管、肾脏、肝脏和肺部,
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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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