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.
人类纤维化病症影响许多器官系统,包括心脏、血管、肾、肝和肺,
在美国,由于过度的疾病负担,包括我们的退伍军人管理局(VA)患者,
人口最常见的纤维化肺病,特发性肺纤维化(IPF),其特征在于:
过度瘢痕组织形成和肺实质的不可逆破坏,导致气体交换
最终导致呼吸衰竭。老龄化是IPF最强的风险因素;然而,
与年龄相关的纤维化疾病易感性的细胞/分子机制仅
开始被探索。提高对衰老在这种疾病中作用的认识将有助于
开发具有更高临床疗效的新疗法。
为了支持VA优异奖的更新申请,我们最近为我们的
了解肺损伤和修复机制中的衰老机制。IPF人类受试者表达
在肌纤维母细胞灶和从IPF分离的离体成纤维细胞中,线粒体sirtuin,SIRT 3水平低
肺SIRT 3的这种下调在小鼠非消退性纤维化的衰老模型中复制;
年轻小鼠中的纤维化在博来霉素后2-4个月基本上消退,老年小鼠表现出持续的纤维化。
我们的数据表明,年轻小鼠的这种纤维化消退能力与SIRT 3的恢复有关。
在肺损伤的后期修复阶段,这一点在老年小鼠中不存在。然而,
SIRT 3(通过肺靶向非病毒cDNA质粒递送)恢复老年人纤维化消退的能力
小鼠这种保护作用与FoxO 3a的体内激活有关,这一点可以通过较高水平的FoxO 3a来证明。
核FoxO 3a。细胞衰老和促纤维化细胞因子转化生长因子-β1(TGF-β 1)
β1)诱导SIRT 3和FoxO 3a下调,导致线粒体功能障碍,
肺成纤维细胞的衰老和凋亡抵抗。我们的研究也支持这样一种可能性,
肺泡巨噬细胞中SIRT 3的调节通过旁分泌调节FoxO 3a的成纤维细胞活化
机制此外,组蛋白乙酰转移酶,p300和环AMP反应元件结合,
CREB结合蛋白(CBP)参与TGF-β1对SIRT 3的表观遗传下调
和细胞衰老。SIRT 3-FoxO 3a信号传导轴的活化受损促进衰老,
抗纤维化的成纤维细胞表型,导致持续性/非消退性纤维化。
在这项拨款申请中要检验的中心假设是,持续性/非消退性纤维化
与衰老相关的是由成纤维细胞中Foxo 3a的活化受损介导的,
成纤维细胞本身或巨噬细胞衍生的旁分泌机制,有助于线粒体
肺成纤维细胞的功能障碍、衰老和凋亡抵抗。
我们的具体目标是:(1)阐明肺组织中SIRT 3的p300/CBP依赖的表观遗传调控
成纤维细胞和肺泡巨噬细胞介导的前分辨率表型;(2)研究的作用,
SIRT 3-FoxO 3a信号轴在恢复线粒体生物能量学和细胞凋亡易感性中的作用
衰老/纤维化的肺成纤维细胞;和(3)确定是否由SIRT 3重建,
遗传/药理学方法通过激活FoxO 3a促进老年小鼠的纤维化消退,
肺成纤维细胞完成本提案中的目标将:(a)揭示表观遗传机制,
控制SIRT 3表达与细胞衰老/老化;(B)提供对SIRT 3的作用的机制见解,
SIRT 3-FoxO 3a信号传导在线粒体生物能量学和细胞可塑性/命运的调节中;和(c)
阐明促消退巨噬细胞的巨噬细胞-成纤维细胞串扰和SIRT 3调节;和(d)提供
SIRT 3-FoxO 3a信号通路的激活促进纤维化消退,
治疗进展性肺病的新方法。
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
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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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