Cadmium-potentiated metabolic reprogramming in pathogenesis of lung fibrosis

镉增强的代谢重编程在肺纤维化发病机制中的作用

• 批准号: 10457414
• 负责人: Young-Mi Go Kang
• 金额: $ 43.88万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10457414
• 关键词: Affect; Age; Antioxidants; Asthma; Autophagocytosis; Biology; Bronchiolitis; Cadmium; Cell Proliferation; Cell Survival; Cell model; Cells; Cellular biology; Cessation of life; Communities; Complex; Cysteine; Data; Development; Diet; Dose; Elderly; Energy Metabolism; Environmental Impact; Excision; Experimental Animal Model; Exposure to; FRAP1 gene; Fatty Acids; Fibroblasts; Fibrosis; Food; Glycolysis; Hospitalization; Human; Infant; Infection; Inflammation; Inflammatory; Interstitial Lung Diseases; Link; Lipids; Literature; Lung; Lung diseases; Measures; Mediating; Metabolic; Metabolic stress; Metals; Methods; Mitochondria; Mitochondrial Proteins; Molecular; Molecular Target; Morbidity - disease rate; Mus; Oxidants; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathology; Pathway Analysis; Pathway interactions; Pharmacology; Pneumonia; Poison; Population; Post-Translational Protein Processing; Predisposition; Protein S; Proteins; Proteome; Public Health; Pulmonary Fibrosis; Research; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Risk; Role; Severities; Signal Transduction; Structure; TXN gene; Testing; Toxic effect; Transcript; Virus Diseases; Zinc Fingers; base; cell growth; disease registry; experience; fatty acid biosynthesis; fatty acid metabolism; genetic manipulation; high risk infant; human morbidity; human mortality; inhibitor; lipid biosynthesis; lipid metabolism; lung injury; metabolome; mitochondrial dysfunction; mitochondrial metabolism; mouse model; non-smoker; non-smoking; oxidation; palmitoylation; protein function; protein metabolite; pulmonary function; response; senescence; transcriptome

Title: Cadmium-potentiated metabolic reprogramming in pathogenesis of lung fibrosis Project Summary Cd is a toxic environmental metal contaminant, number 7 on Agency for Toxic Substances and Disease Registry (ATSDR) Substance Priority List. Lung diseases are extremely common. Our previous study shows that lung Cd burden found in non-smoker's lung caused changes in the mouse lung metabolome, transcriptome and redox proteome with effects on airway reactivity, glycolysis and lipid metabolism, inflammation and fibrotic signaling. This has considerable implications for risk of pulmonary fibrosis and other interstitial lung diseases. Humans do not have an efficient mechanism for Cd removal; thus, Cd burden in humans increases with age. Respiratory syncytial virus (RSV) is a major cause of bronchiolitis in infants and causes considerable morbidity due to subsequent development of asthma in elderly. Our previous integrated omics analyses of low-dose Cd toxicity in lung showed association with zinc finger DHHC domain-containing palmitoyltransferase zDHHC11 and Cd-dependent response with activation of mTORC1 signaling, linked to lung fibrosis. Integrated network responses of metabolome to low dose Cd exposure with RSV infection showed mitochondrial dysfunction with disrupted energy metabolism and fatty acid biosynthesis as critical intermediate responses in Cd-dependent lung injury. Based on our findings and available data, we hypothesize that 1) infant RSV infection reprograms protein S-palmitoylation as an activator of mTORC1; 2) Cd reprograms mitochondrial metabolism and redox signaling to create a sustained driver of mTORC1 activity; 3) the combination of mTORC1 activators creates a vicious cycle because mTORC1 activates S-palmitoylation; 4) sustained mTORC1 activity causes lung fibrosis. We propose three Aims to test these mechanisms using molecular, cell biology, pathology and omics methods in mice and cultured lung cells with controlled Cd dosing. Aim 1 will determine whether Cd potentiates RSV-induced protein S-palmitoylation via regulating the activity of key proteins, zDHHC11, acyl protein thioesterase. Aim 2 is to examine the role of mTORC1 in Cd-potentiated fibrosis pathways using mouse and cell models. Aim 3 will test whether lung Cd burden serves as a driver for fibrosis following RSV infection by effects on mitochondria and activation of mTORC1 signaling. Targeted analyses will provide direct tests of the proposed mechanisms for low-dose Cd and RSV infection in lung fibrosis. The integrated omics approaches will additionally provide the first detailed look at the central network and sub-network structures, and identify molecular communities linked to lung responses to low-dose Cd in mice with prior RSV infection. The results will have sustained impact by providing an experimental animal model to study interactions of low intensity exposures in lung disease and by demonstrating whether low-dose environmental Cd interacts with RSV infection to increase lung fibrosis through disrupting the protein S- palmitoylation mechanism, altering mTORC1 activation and increasing mitochondrial oxidative stress.

标题：镉增强的代谢重编程在肺纤维化发病机制中的作用 项目摘要 镉是一种有毒的环境金属污染物，在有毒物质和疾病机构中排名第7位 美国毒物与疾病登记署（ATSDR）物质优先列表。肺部疾病非常常见。我们之前的研究表明 在非吸烟者的肺中发现的肺镉负荷引起小鼠肺代谢组的变化， 转录组和氧化还原蛋白质组对气道反应性、糖酵解和脂质代谢的影响， 炎症和纤维化信号传导。这对肺纤维化和其他疾病的风险有相当大的影响。 间质性肺病人类没有有效的镉去除机制，因此， 人类随着年龄的增长而增长。呼吸道合胞病毒（RSV）是婴儿毛细支气管炎的主要原因， 由于随后在老年人中发生哮喘，导致相当大的发病率。我们以前的综合 低剂量镉肺毒性的组学分析显示，与锌指DHHC结构域相关， 棕榈酰转移酶zDHHC 11和镉依赖性反应与mTORC 1信号传导的激活，与 肺纤维化呼吸道合胞病毒感染下低剂量镉暴露代谢组的整合网络响应 显示线粒体功能障碍，能量代谢和脂肪酸生物合成中断是关键 镉依赖性肺损伤的中间反应。根据我们的发现和现有数据，我们假设 1）婴儿RSV感染重编程蛋白S-棕榈酰化作为mTORC 1的激活剂; 2）Cd重编程 线粒体代谢和氧化还原信号传导，以产生mTORC 1活性的持续驱动; 3） mTORC 1激活剂的组合产生恶性循环，因为mTORC 1激活S-棕榈酰化; 4） 持续的mTORC 1活性导致肺纤维化。我们提出了三个目标来测试这些机制， 分子、细胞生物学、病理学和组学方法在小鼠和培养的肺细胞与控制镉剂量。 目的1将确定镉是否通过调节蛋白的活性来增强RSV诱导的蛋白S-棕榈酰化。 关键蛋白，zDHHC 11，酰基蛋白硫酯酶。目的2是研究mTORC 1在镉增强的细胞凋亡中的作用。 使用小鼠和细胞模型的纤维化途径。目标3将测试肺镉负荷是否作为驱动因素， 通过对线粒体的影响和mTORC 1信号传导的激活，RSV感染后纤维化。针对性 分析将提供对低剂量Cd和RSV感染肺部的拟议机制的直接测试 纤维化综合组学方法还将提供对中央网络的第一次详细观察 和子网络结构，并确定与肺对低剂量镉的反应有关的分子群落， 先前感染RSV的小鼠。研究结果将产生持续的影响， 研究低强度照射在肺部疾病中的相互作用的模型， 环境Cd与RSV感染相互作用，通过破坏蛋白S- 棕榈酰化机制，改变mTORC 1活化和增加线粒体氧化应激。