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)是一种衰老性疾病。IPF的发病率和死亡率较高,中位生存率不到3年。IPF的发病率和患病率随着年龄的增长而急剧增加;然而,尽管存在这种强烈的相关性,但尚未阐明导致纤维化疾病的衰老易感性的细胞/分子机制。 我们实验室最近的研究已经鉴定了活性氧(ROS)生成酶NADPH氧化酶-4(Nox 4),其在介导成纤维细胞(Fbs)向肌成纤维细胞(MFbs)分化中,肌成纤维细胞(MFbs)是纤维发生的关键效应物,并且在肺损伤的鼠模型中在体内肺纤维化中。我们的初步研究表明,Nox 4的生物学作用可能是由SIRT 3,线粒体sirtuin的表达调节。细胞衰老和TGF-β1都介导SIRT 3的抑制;我们的初步研究支持SIRT 3的表观遗传沉默的作用,涉及DNA甲基化和组蛋白修饰。SIRT 3的表达减少促进衰老和促纤维化Fb表型。TGF-β1诱导的SIRT 3下调与线粒体蛋白的超乙酰化相关,支持MFbs中线粒体生物能量学改变的作用。患有IPF的人类受试者在成肌纤维细胞灶中(通过免疫组织化学)以及在从IPF肺分离的离体Fbs中表达低水平的SIRT 3。我们已经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后4个月消退>50%,而老年小鼠(18个月)显示出持续的纤维化反应。虽然SIRT 3水平在两组的纤维化阶段下降,但年轻小鼠表现出在消退期间恢复SIRT 3水平的能力;相反,老年小鼠表现出SIRT 3的持续下调。 在该资助提案中要测试的中心假设是,在衰老的背景下,肺损伤导致持续的、表观遗传调节的SIRT 3沉默,其导致线粒体功能障碍、MFb衰老和凋亡抗性,导致随着衰老的持续纤维化。 我们的具体目标是:(1)确定SIRT 3下调与细胞衰老和肺Fbs中TGF-β1信号传导的表观遗传机制;(2)确定SIRT 3在调节线粒体生物能量学、Fb衰老和凋亡抗性中的作用;(3)确定全动物SIRT 3敲除和/或胶原产生/间充质细胞中SIRT 3的条件性遗传缺失是否诱导幼龄小鼠中的持续纤维化。 完成本提案中的目标将:(a)阐明控制SIRT 3表达与细胞衰老/老化的表观遗传机制;(B)提供SIRT 3在维持线粒体生物能量学和细胞可塑性/命运中的作用的机制见解;(c)提供在年龄相关性纤维化的背景下SIRT 3诱导促进纤维化消退的概念验证,揭示了一种新的治疗方法,以解决非解决纤维化疾病,如IPF。
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)
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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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