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Metabolic dysfunction regulates mitophagy-dependent necroptosis in COPD

代谢功能障碍调节 COPD 中线粒体自噬依赖性坏死性凋亡

基本信息

批准号：
9566374
负责人：
Augustine M Choi
金额：
$ 4.97万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9566374
关键词：
Address Affect Apoptosis Autoimmunity Autophagocytosis Biogenesis Bronchitis Cell Death Chronic Obstructive Airway Disease Chronic lung disease Complex Degradation Pathway Development Disease Epithelial Cells Experimental Models Fatty Acids Functional disorder Human Impairment Individual Infection Inflammation Lung Lung diseases Lysosomes Membrane Potentials Metabolic Metabolic Pathway Mitochondria Mitochondrial DNA Mitochondrial Swelling Mus Organelles Outcome Oxidative Phosphorylation Oxidative Stress PINK1 gene Pathogenesis Pathogenicity Pathway interactions Patients Peptide Hydrolases Process Production Protease Inhibitor Proteins Publishing Pulmonary Emphysema Reactive Oxygen Species Regulation Resistance Risk Factors Smoking History Testing Tissues cell growth regulation cell injury cigarette smoking effective therapy environmental tobacco smoke exposure functional disability metabolic profile mitochondrial autophagy mitochondrial dysfunction mortality pathogen programs response therapy development

项目摘要

PROJECT SUMMARY The mechanisms underlying the pathogenesis of chronic obstructive pulmonary disease (COPD), primarily associated with cigarette smoking (CS), including emphysema and bronchitis, remain unclear. Our published studies have suggested that autophagy, a lysosome-dependent pathway for the degradation of organelles and proteins, represents a major cellular and tissue response to CS exposure, in both experimental and human COPD lung. Emerging studies suggest that autophagy, while well established as a cellular survival process, can exert homeostatic or detrimental effects in complex diseases. Our studies were the first to demonstrate deleterious effects of autophagy and mitochondrial autophagy (mitophagy) in experimental models of COPD. Mice genetically deficient in the mitophagy regulator PINK1 were resistant to experimental COPD. We discovered that mitophagy induced by CS in response to mitochondrial dysfunction activates programmed epithelial cell death, in particular the necroptosis mode of cell death. Our Preliminary Studies indicate that CS exposure can disrupt metabolic pathways, including dysregulation of oxidative phosphorylation (OXPHOS) and inhibition of fatty acid (FA) synthesis. Hence, we put forth the following Hypothesis: CS exposure causes epithelial cell metabolic disruption and impaired FA synthesis that causes mitochondrial dysfunction, leading to activation of PINK1-dependent mitophagy. Mitophagy in turn drives a pro-pathogenic mechanism dependent on the activation of necroptosis. Activation of this mitophagy-dependent necroptosis pathway in response to metabolic and mitochondrial dysfunction may adversely affect airway function and emphysema outcomes during CS-induced COPD pathogenesis. To test this hypothesis, we will address three Specific Aims: Specific Aim 1: To determine the mechanisms by which CS induces mitophagy in the lung. Specific Aim 2: To determine the effect of impaired OXPHOS and FA synthesis on the regulation of mitochondrial dynamics and biogenesis and their impact on experimental COPD. Specific Aim 3: To determine the regulation of cellular necroptosis by CS, and its impact on lung functional impairment in experimental models of COPD.

项目概要慢性阻塞性肺疾病（COPD）的发病机制主要是与吸烟（CS）相关的疾病，包括肺气肿和支气管炎，仍不清楚。我们发表的研究表明，自噬是一种依赖于溶酶体的细胞器降解途径蛋白质，代表了实验和人体对 CS 暴露的主要细胞和组织反应慢性阻塞性肺病肺。新兴研究表明，自噬虽然已被确定为细胞生存过程，但可以对复杂疾病产生稳态或有害影响。我们的研究首先证明了自噬和线粒体自噬（mitophagy）对慢性阻塞性肺病（COPD）实验模型的有害影响。线粒体自噬调节因子 PINK1 基因缺陷的小鼠对实验性慢性阻塞性肺病具有抵抗力。我们发现由 CS 诱导的线粒体自噬响应线粒体功能障碍激活程序化上皮细胞死亡，特别是细胞死亡的坏死性凋亡模式。我们的初步研究表明，CS 暴露会扰乱代谢途径，包括氧化磷酸化 (OXPHOS) 失调和抑制脂肪酸（FA）合成。因此，我们提出以下假设：CS暴露导致上皮细胞代谢紊乱和 FA 合成受损，导致线粒体功能障碍，导致 PINK1 依赖性线粒体自噬的激活。线粒体自噬进而驱动依赖于的促致病机制坏死性凋亡的激活。激活这种线粒体自噬依赖性坏死性凋亡途径代谢和线粒体功能障碍可能会对气道功能和肺气肿结局产生不利影响 CS诱发的COPD发病机制。为了检验这一假设，我们将解决三个具体目标：具体目标 1：确定 CS 诱导肺部线粒体自噬的机制。具体目标 2：确定 OXPHOS 和 FA 合成受损对线粒体动力学和生物合成调节的影响它们对实验性慢性阻塞性肺病的影响。具体目标 3：确定 CS 对细胞坏死性凋亡的调节，及其对慢性阻塞性肺病实验模型中肺功能损伤的影响。