The role of SIRT3 inducers in preventing alveolar epithelial cell death and lung fibrosis
The role of SIRT3 inducers in preventing alveolar epithelial cell death and lung fibrosis
批准号:
9379398
负责人:
Renea Poppino Jablonski
金额:
$3.37万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-01 至 2018-02-28
关键词:
8-Oxoguanine DNA GlycosylaseAcetylationAconitate HydrataseAgingAlveolarAntioxidantsApoptosisAsbestosAsbestosisAttenuatedBiological PreservationBleomycinBreast Epithelial CellsCell DeathCellsCessation of lifeChromatin StructureCitric Acid CycleComplexDNA DamageDNA RepairDataDeacetylaseDevelopmentDiseaseDisease ProgressionElectron TransportEnergy MetabolismEpithelialEpithelial CellsEpitheliumEquilibriumEventExposure toFDA approvedFamilyFibrosisGenomeGenome StabilityHamman-Rich syndromeHistone DeacetylationHumanHydrogen PeroxideIn VitroInjuryInvestigationLeadLungLung diseasesMaintenanceMediatingMesenchymalMetabolicMitochondriaMitochondrial DNAMitochondrial ProteinsMusNatureOGG1 geneOxidantsOxidative StressPathogenesisPathway interactionsPatientsPlayPreparationPreventionProductionProtein AcetylationPulmonary FibrosisReportingRespiratory physiologyResveratrolRoleSOD2 geneSirtuinsSmall Interfering RNATNF geneTP53 geneTestingTherapeuticTransforming Growth Factor betaTranslatingage relatedalveolar epitheliumalveolar type II cellanti agingantioxidant enzymecoronary fibrosisexperiencehonokiolin vivoinsightlung injurymembermitochondrial dysfunctionmitochondrial genomenovelnovel therapeuticspreventprotective effectprotein expressionsmall molecule
中文摘要
项目总结/文摘
英文摘要
Project Summary/Abstract
The pathogenesis of age-related idiopathic pulmonary fibrosis (IPF) and asbestosis is complex and
incompletely understood, though accumulating evidence firmly implicates mitochondrial DNA (mtDNA) damage
that lead to alveolar epithelial cell (AEC) apoptosis as a key event in disease development. We previously
showed that the extent of AEC mtDNA damage, mitochondrial aconitase (ACO-2) depletion and apoptosis are
critical determinants of the fibrogenic potential of asbestos. Sirtuin 3 (SIRT3) is the major mitochondrial
deacetylase and considered the “guardian of the mitochondrial genome” through its role in regulating
mitochondrial proteins that detoxify oxidative stress and preserve mtDNA via modulation of mitochondrial 8-
oxoguanine DNA glycosylase (OGG1) and ACO-2 activities. Our preliminary studies in preparation for this
proposal show that oxidative stress (asbestos or H2O2) decreases AEC SIRT3 protein expression; that SIRT3
silencing augments while SIRT3 enforced expression (EE) attenuates oxidant-induced AEC ACO-2 depletion,
mtDNA damage, and apoptosis; that SIRT3 deficiency enhances asbestos- and bleomycin-induced pulmonary
fibrosis in association with increased AEC mtDNA damage; and that lungs from patients with idiopathic
pulmonary fibrosis (IPF) have increased acetylation of OGG1 and MnSOD. Taken together, these data
suggest a novel role for SIRT3 in the maintenance of a healthy alveolar epithelium and prevention of fibrotic
lung diseases. We hypothesize that honokiol, a small molecule SIRT3 inducer, attenuates oxidant-induced
AEC mtDNA damage, mitochondrial ROS production, and apoptosis as well as pulmonary fibrosis in part by
maintaining expression and activity of OGG1, ACO-2, and MnSOD. We have formulated two related aims to
test this hypothesis. In Aim 1, we will determine whether honokiol prevents oxidant-induced AEC mtDNA
damage and intrinsic apoptosis in vitro via a SIRT3-dependent mechanism involving preservation of AEC
mitochondrial protein (OGG1, ACO-2, MnSOD) function and reduction in protein acetylation and mitochondrial
ROS. In Aim 2, we will use wild-type and Sirt3-/- mice to determine whether honokiol and resveratrol (another
small molecule sirtuin inducer) mitigate pulmonary fibrosis (asbestos or bleomycin) in vivo by a SIRT3-
dependent mechanism and whether protection is associated with reductions in alveolar epithelial type 2 cell
(AT2) OGG1 and MnSOD acetylation, mtDNA damage, and apoptosis. These studies will elucidate the
importance of honokiol-induced SIRT3-EE in preserving AT2 cell mtDNA integrity and preventing lung fibrosis
which may have broad implications for the treatment of IPF and other fibrotic lung diseases.
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