The role of SIRT3 inducers in preventing alveolar epithelial cell death and lung fibrosis

SIRT3诱导剂在预防肺泡上皮细胞死亡和肺纤维化中的作用

基本信息

批准号：
9379398
负责人：
Renea Poppino Jablonski
金额：
$ 3.37万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2016-09-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9379398
关键词：
8-Oxoguanine DNA Glycosylase Acetylation Aconitate Hydratase Aging Alveolar Antioxidants Apoptosis Asbestos Asbestosis Attenuated Biological Preservation Bleomycin Breast Epithelial Cells Cell Death Cells Cessation of life Chromatin Structure Citric Acid Cycle Complex DNA Damage DNA Repair Data Deacetylase Development Disease Disease Progression Electron Transport Energy Metabolism Epithelial Epithelial Cells Epithelium Equilibrium Event Exposure to FDA approved Family Fibrosis Genome Genome Stability Hamman-Rich syndrome Histone Deacetylation Human Hydrogen Peroxide In Vitro Injury Investigation Lead Lung Lung diseases Maintenance Mediating Mesenchymal Metabolic Mitochondria Mitochondrial DNA Mitochondrial Proteins Mus Nature OGG1 gene Oxidants Oxidative Stress Pathogenesis Pathway interactions Patients Play Preparation Prevention Production Protein Acetylation Pulmonary Fibrosis Reporting Respiratory physiology Resveratrol Role SOD2 gene Sirtuins Small Interfering RNA TNF gene TP53 gene Testing Therapeutic Transforming Growth Factor beta Translating age related alveolar epithelium alveolar type II cell anti aging antioxidant enzyme coronary fibrosis experience honokiol in vivo insight lung injury member mitochondrial dysfunction mitochondrial genome novel novel therapeutics prevent protective effect protein expression small molecule

项目摘要

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.

项目摘要/摘要与年龄相关的特发性肺纤维化（IPF）和石棉病的发病机理是复杂的，并且尽管积累了证据，但不完全理解的是线粒体DNA（mtDNA）损伤这导致肺泡上皮细胞（AEC）凋亡是疾病发育中的关键事件。我们以前表明AEC mtDNA损伤，线粒体刺激酶（ACO-2）的部署和凋亡的程度是石棉的纤维化潜力的关键决定剂。 Sirtuin 3（SIRT3）是主要的线粒体脱乙酰基酶，并通过其在调节中的作用来视为“线粒体基因组的守护者” 线粒体蛋白可以通过调节线粒体8-的调节来解毒并保留mtDNA 氧气DNA糖基酶（OGG1）和ACO-2活性。我们为此做准备的初步研究提案表明，氧化应激（石棉或H2O2）降低了AEC SIRT3蛋白表达。那个sirt3 SIRT3强制表达（EE）减轻增强（EE）会减轻氧化诱导的AEC ACO-2部署， mtDNA损伤和凋亡； SIRT3缺乏增强了石棉和博来霉素诱导的肺纤维化与AEC mtDNA损伤增加；并且是特发性患者的肺肺纤维化（IPF）的乙酰化增加了OGG1和MNSOD。综上所述，这些数据提出SIRT3在维持健康的肺泡上皮和预防纤维化中的新作用肺部疾病。我们假设一种小分子SIRT3诱导剂Honokiol减弱了氧化剂诱导的 AEC mtDNA损伤，线粒体ROS的产生和凋亡以及肺纤维化部分部分由维持OGG1，ACO-2和MNSOD的表达和活性。我们已经提出了两个相关的目标检验此假设。在AIM 1中，我们将确定Honokiol是否可以防止氧化剂诱导的AEC mtDNA 通过SIRT3依赖性机制在体外损害和固有凋亡，涉及保存AEC 线粒体蛋白（OGG1，ACO-2，MNSOD）的功能和蛋白乙酰化和线粒体的降低罗斯。在AIM 2中，我们将使用野生型和sirt3 - / - 鼠标来确定Honokiol和白藜芦醇是否（另一个小分子sirtuin诱导蛋白）在体内减轻肺纤维化（石棉或博来霉素）。依赖机制以及保护是否与肺泡上皮2型细胞减少有关（AT2）OGG1和MNSOD乙酰化，mtDNA损伤和凋亡。这些研究将阐明 Honokiol诱导的SIRT3-EE在保持AT2细胞MTDNA完整性和防止肺纤维化方面的重要性这可能对IPF和其他纤维化肺部疾病的治疗具有广泛的影响。