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:
- 金额:$ 4.97万
- 依托单位:
- 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:
- 关键词:AddressAffectApoptosisAutoimmunityAutophagocytosisBiogenesisBronchitisCell DeathChronic Obstructive Airway DiseaseChronic lung diseaseComplexDegradation PathwayDevelopmentDiseaseEpithelial CellsExperimental ModelsFatty AcidsFunctional disorderHumanImpairmentIndividualInfectionInflammationLungLung diseasesLysosomesMembrane PotentialsMetabolicMetabolic PathwayMitochondriaMitochondrial DNAMitochondrial SwellingMusOrganellesOutcomeOxidative PhosphorylationOxidative StressPINK1 genePathogenesisPathogenicityPathway interactionsPatientsPeptide HydrolasesProcessProductionProtease InhibitorProteinsPublishingPulmonary EmphysemaReactive Oxygen SpeciesRegulationResistanceRisk FactorsSmoking HistoryTestingTissuescell growth regulationcell injurycigarette smokingeffective therapyenvironmental tobacco smoke exposurefunctional disabilitymetabolic profilemitochondrial autophagymitochondrial dysfunctionmortalitypathogenprogramsresponsetherapy 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.
项目摘要
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,尚不清楚。我们的出版
研究表明,自噬,一种溶酶体依赖的细胞器降解途径,
蛋白质,代表了实验动物和人体对CS暴露的主要细胞和组织反应
慢性阻塞性肺病新兴的研究表明,自噬,虽然作为一种细胞生存过程,
在复杂疾病中发挥稳态或有害作用。我们的研究首次证明
自噬和线粒体自噬(mitophagy)在COPD实验模型中的有害作用。
线粒体自噬调节因子PINK1基因缺陷的小鼠对实验性COPD有抵抗力。我们
发现CS诱导的线粒体自噬响应于线粒体功能障碍激活程序化的
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,
暴露可破坏代谢途径,包括氧化磷酸化(OXPHOS)失调,
抑制脂肪酸(FA)合成。因此,我们提出以下假设:CS暴露导致
上皮细胞代谢破坏和FA合成受损,导致线粒体功能障碍,
PINK1依赖性线粒体自噬的激活。线粒体自噬反过来驱动一种依赖于
坏死性凋亡的激活这种线粒体自噬依赖性坏死性凋亡途径的激活是对
代谢和线粒体功能障碍可能会对气道功能和肺气肿的结果产生不利影响,
CS诱导的COPD发病机制。为了验证这一假设,我们将讨论三个具体目标:具体目标1:
确定CS诱导肺线粒体自噬的机制。具体目标2:确定
受损的OXPHOS和FA合成对线粒体动力学和生物发生调节的影响,
对实验性COPD的影响具体目的3:确定CS对细胞坏死性凋亡的调节,
及其对COPD实验模型肺功能损害的影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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专利数量(0)
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Augustine M Choi其他文献
Augustine M Choi的其他文献
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{{ truncateString('Augustine M Choi', 18)}}的其他基金
A Phase 1b Study of Inhaled CO for the Treatment of Sepsis-Induced ARDS
吸入 CO 治疗脓毒症引起的 ARDS 的 1b 期研究
- 批准号:
10028004 - 财政年份:2020
- 资助金额:
$ 4.97万 - 项目类别:
Multidisciplinary Approach Training in Respiratory Research
呼吸研究多学科方法培训
- 批准号:
10348195 - 财政年份:2018
- 资助金额:
$ 4.97万 - 项目类别:
Multidisciplinary Approach Training in Respiratory Research
呼吸研究多学科方法培训
- 批准号:
10555619 - 财政年份:2018
- 资助金额:
$ 4.97万 - 项目类别:
Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
吸烟者纤维化和肺气肿的独特和重叠途径
- 批准号:
10172307 - 财政年份:2013
- 资助金额:
$ 4.97万 - 项目类别:
Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
吸烟者纤维化和肺气肿的独特和重叠途径
- 批准号:
9300997 - 财政年份:2013
- 资助金额:
$ 4.97万 - 项目类别:
Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
吸烟者纤维化和肺气肿的独特和重叠途径
- 批准号:
8476322 - 财政年份:2013
- 资助金额:
$ 4.97万 - 项目类别:
Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
吸烟者纤维化和肺气肿的独特和重叠途径
- 批准号:
10636890 - 财政年份:2013
- 资助金额:
$ 4.97万 - 项目类别:
Mitochondrial Dysfunction and Metabolic Regulation of the Necroptosis Pathway in COPD and IPF
COPD 和 IPF 中坏死性凋亡途径的线粒体功能障碍和代谢调节
- 批准号:
10636900 - 财政年份:2013
- 资助金额:
$ 4.97万 - 项目类别:
Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
吸烟者纤维化和肺气肿的独特和重叠途径
- 批准号:
9113651 - 财政年份:2013
- 资助金额:
$ 4.97万 - 项目类别:
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