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.

项目概要/摘要与年龄相关的特发性肺纤维化（IPF）和石棉肺的发病机制很复杂，尚未完全了解，但越来越多的证据明确表明线粒体 DNA (mtDNA) 损伤导致肺泡上皮细胞（AEC）凋亡是疾病发展的关键事件。结果表明，AEC mtDNA 损伤、线粒体顺乌头酸酶 (ACO-2) 耗竭和细胞凋亡的程度 Sirtuin 3 (SIRT3) 是石棉纤维化潜力的关键决定因素。脱乙酰酶并通过其在调节中的作用被认为是“线粒体基因组的守护者” 线粒体蛋白通过调节线粒体 8- 解毒氧化应激并保护 mtDNA 我们为此做准备的初步研究。提案表明氧化应激（石棉或 H2O2）会降低 AEC SIRT3 蛋白的表达；沉默增强而 SIRT3 强制表达 (EE) 减弱氧化剂诱导的 AEC ACO-2 耗竭， mtDNA 损伤和细胞凋亡；SIRT3 缺乏会增强石棉和博来霉素诱导的肺损伤纤维化与 AEC mtDNA 损伤增加有关；特发性患者的肺部肺纤维化 (IPF) 增加了 OGG1 和 MnSOD 的乙酰化程度。表明 SIRT3 在维持健康肺泡上皮和预防纤维化方面具有新作用我们相信和厚朴酚是一种小分子 SIRT3 诱导剂，可以减轻氧化剂诱导的肺部疾病。 AEC mtDNA 损伤、线粒体 ROS 产生、细胞凋亡以及肺纤维化部分由维持 OGG1、ACO-2 和 MnSOD 的表达和活性我们制定了两个相关目标。在目标 1 中，我们将确定诺木酚是否可以预防氧化剂诱导的 AEC mtDNA。通过 SIRT3 依赖性机制（涉及 AEC 的保存）进行体外损伤和内在凋亡线粒体蛋白（OGG1、ACO-2、MnSOD）功能以及蛋白质乙酰化和线粒体的减少在目标 2 中，我们将使用野生型和 Sirt3-/- 小鼠来确定和厚朴酚和白藜芦醇（另一种小分子 Sirtuin 诱导剂）通过 SIRT3- 减轻体内肺纤维化（石棉或博莱霉素）依赖机制以及保护是否与肺泡上皮 2 型细胞减少相关 (AT2) OGG1 和 MnSOD 乙酰化、mtDNA 损伤和细胞凋亡。和厚朴酚诱导的 SIRT3-EE 在保护 AT2 细胞 mtDNA 完整性和预防肺纤维化中的重要性这可能对 IPF 和其他纤维化肺部疾病的治疗具有广泛的影响。