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.
描述(由申请人提供)
特发性肺纤维化(IPF)是一种衰老疾病。 IPF 的发病率和死亡率很高,中位生存率不到三年。 IPF 的发病率和患病率随着年龄的增长而急剧增加;然而,尽管存在这种密切的关联,但导致衰老易患纤维化疾病的细胞/分子机制尚未阐明。 我们实验室最近的研究发现,一种活性氧 (ROS) 生成酶 NADPH 氧化酶 4 (Nox4) 在介导成纤维细胞 (Fbs) 向肌成纤维细胞 (MFbs) 的分化(纤维形成的关键效应物)以及小鼠肺损伤模型的体内肺纤维化中发挥作用。我们的初步研究表明,Nox4 的生物学作用可能受到线粒体 Sirtuin SIRT3 表达的调节。细胞衰老和 TGF-β1 都会介导 SIRT3 的抑制;我们的初步研究支持 SIRT3 表观遗传沉默的作用,涉及 DNA 甲基化和组蛋白修饰。 SIRT3 表达的减少会促进衰老和促纤维化的 Fb 表型。 TGF-β1 诱导的 SIRT3 下调与线粒体蛋白的过度乙酰化相关,支持 MFb 中线粒体生物能改变的作用。患有 IPF 的人类受试者在肌纤维母细胞病灶(通过免疫组织化学)以及从 IPF 肺部分离的离体 Fb 中表达低水平的 SIRT3。我们开发了一种新的小鼠非消退性纤维化衰老模型;年轻小鼠(2 个月)的纤维化在博来霉素治疗后 4 个月内消退了 50% 以上,而老年小鼠(18 个月)则表现出持续的纤维化反应。虽然两组小鼠的 SIRT3 水平在纤维化阶段均有所下降,但年轻小鼠表现出在消退期间恢复 SIRT3 水平的能力;相反,老年小鼠表现出 SIRT3 的持续下调。 本拨款提案要测试的中心假设是,在衰老的背景下,肺损伤会导致持续的、表观遗传调节的 SIRT3 沉默,从而导致线粒体功能障碍、MFb 衰老和细胞凋亡抵抗,从而导致衰老过程中的持续纤维化。 我们的具体目标是:(1) 确定 SIRT3 下调与细胞衰老和肺 Fb 中 TGF-β1 信号传导的表观遗传机制; (2)确定SIRT3在调节线粒体生物能、Fb衰老和抗凋亡中的作用; (3) 确定整个动物 SIRT3 敲除和/或胶原蛋白生成细胞/间充质细胞中 SIRT3 的条件性基因缺失是否会诱导幼年小鼠的持续纤维化。 完成本提案中的目标将: (a) 阐明控制 SIRT3 表达与细胞衰老/衰老的表观遗传机制; (b) 提供有关 SIRT3 在维持线粒体生物能学和细胞可塑性/命运中的作用的机制见解; (c) 提供概念证明,证明在年龄相关的纤维化背景下诱导 SIRT3 有助于纤维化消退,从而揭示了一种针对 IPF 等非消退性纤维化疾病的新治疗方法。
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
- 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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