Cadmium-potentiated metabolic reprogramming in pathogenesis of lung fibrosis

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 Cd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七 登记册(ATSDR)物质优先列表。肺部疾病是非常常见的。我们之前的研究表明 在非吸烟者肺中发现的肺镉负荷导致了小鼠肺代谢物的变化， 转录组和氧化还原蛋白质组对呼吸道反应性、糖酵解和脂代谢的影响 炎症和纤维化信号。这对肺纤维化和其他疾病的风险有很大影响 间质性肺病。人类没有一种有效的机制来去除镉；因此，镉在人体内的负担 人类随着年龄的增长而增加。呼吸道合胞病毒(RSV)是婴幼儿毛细支气管炎的主要病因 由于随后在老年人中发展为哮喘，导致相当大的发病率。我们之前集成的 低剂量镉肺毒性的组学分析表明与含锌指DHHC结构域有关 棕榈酰基转移酶zDHHC11和激活mTORC1信号的CD依赖反应，与 肺纤维化。代谢组对低剂量镉暴露合并呼吸道合胞病毒感染的整合网络反应 显示线粒体功能障碍，能量代谢和脂肪酸生物合成中断为关键 镉依赖肺损伤的中间反应。基于我们的发现和可用的数据，我们假设 1)婴儿呼吸道合胞病毒感染重编程S-棕榈酰化蛋白作为mTORC 1的激活剂；2)CD重编程 线粒体新陈代谢和氧化还原信号，以创建mTORC1活动的持续驱动；3) MTORC_1激活剂的结合造成恶性循环，因为mTORC_1激活S-棕榈酰化；4) 持续的mTORC1活动会导致肺纤维化。我们提出了三个目标来测试这些机制： 控制镉剂量的小鼠和培养肺细胞的分子、细胞生物学、病理学和组学方法。 目的1确定镉是否通过调节呼吸道合胞病毒诱导的蛋白S棕榈酰化活性而增强其活性。 关键蛋白zDHHC11、酰基蛋白硫代酯酶。目的2是研究mTORC1在CD增强中的作用 使用小鼠和细胞模型的纤维化途径。Aim 3将测试肺Cd负担是否为驱动因素 呼吸道合胞病毒感染后的纤维化通过影响线粒体和激活mTORC1信号来实现。目标明确 分析将为低剂量镉和呼吸道合胞病毒肺部感染的拟议机制提供直接测试。 纤维化症。集成的组学方法还将提供对中心网络的第一个详细了解 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 有呼吸道合胞病毒感染史的小鼠。通过提供一种实验动物，这一结果将产生持续的影响 研究肺部疾病中低强度暴露相互作用的模型，并通过论证低剂量 环境镉通过破坏S蛋白与呼吸道合胞病毒感染相互作用增加肺纤维化 棕榈酰化机制，改变mTORC1的激活和增加线粒体的氧化应激。

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.