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

基本信息

批准号：
10292332
负责人：
Young-Mi Go Kang
金额：
$ 46.69万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/10292332
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/antagonist 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

项目摘要

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：镉启用的代谢重编程在肺纤维化的发病机理中项目摘要 CD是一种有毒的环境金属污染物，在有毒物质和疾病的代理机构中排名第7 注册表（ATSDR）物质优先级。肺部疾病非常普遍。我们以前的研究表明在非吸烟肺中发现的肺CD负担导致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的风险具有相当大的意义间质性肺部疾病。人没有有效的CD去除机制；因此，CD负担人类随着年龄的增长而增加。呼吸道合胞病毒（RSV）是婴儿和由于随后的老年人哮喘的发展，引起了相当大的发病率。我们以前的整合肺中低剂量CD毒性的OMICS分析显示与含锌指DHHC结构域的含量相关棕榈酰转移酶ZDHHC11和CD依赖性响应，并激活MTORC1信号，与与肺纤维化。与RSV感染的代谢组对低剂量CD暴露的集成网络响应表现出线粒体功能障碍，能量代谢中断和脂肪酸生物合成为关键 CD依赖性肺损伤中的中间反应。根据我们的发现和可用数据，我们假设 1）婴儿RSV感染重编程将蛋白质S-膜酰化作为MTORC1的激活剂； 2）CD重编程线粒体代谢和氧化还原信号传导，以创建MTORC1活性的持续驱动力； 3） MTORC1激活剂的组合会产生一个恶性循环，因为MTORC1激活S-膜酰基化。 4）持续的MTORC1活性会导致肺纤维化。我们提出了三个目的，以使用小鼠和培养的肺细胞中的分子，细胞生物学，病理学和魔法方法，具有受控的CD剂量。 AIM 1将确定CD是否通过调节活性来增强RSV诱导的蛋白S-膜酰化关键蛋白，ZDHHC11，酰基蛋白硫酯酶。 AIM 2是检查MTORC1在CD启用中的作用使用小鼠和细胞模型的纤维化途径。 AIM 3将测试肺CD负担是否充当驱动器 RSV感染后通过对线粒体的影响和MTORC1信号传导激活后的纤维化。目标分析将直接测试肺中低剂量CD和RSV感染所提出的机制纤维化。集成的OMICS方法还将为中央网络提供第一个详细的外观和子网络结构，并确定与肺对低剂量CD的反应有关的分子群落患有先前RSV感染的小鼠。结果将通过提供实验动物来持续影响研究低强度暴露在肺病中的相互作用并通过证明低剂量的相互作用的模型环境CD与RSV感染相互作用，通过破坏蛋白质S-来增加肺纤维化棕榈酰化机制，改变了MTORC1激活并增加了线粒体氧化应激。