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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.

项目总结