Cytoplasmic-nuclear redox signaling: Disruption by dietary cadmium levels

细胞质-核氧化还原信号传导：膳食镉水平的干扰

• 批准号: 8761505
• 负责人: Young-Mi Go Kang
• 金额: $ 35.1万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761505
• 关键词: Actins; Affect; Alveolar; American; Anemia; Basic Science; Binding Proteins; Biological; Biological Models; Biology; Bleomycin; Breathing; Cadmium; Calcium; Calibration; Cell Nucleus; Cell model; Cells; Chemosensitization; Chronic; Chronic Disease; Confounding Factors (Epidemiology); Cysteine; Cytoskeleton; Data; Dependence; Diet; Dietary Cadmium; Dietary intake; Disease; Disease model; Dose; Elements; Environment; Environmental Exposure; Epidemiologic Studies; Epithelial Cells; Etiology; Evaluation; Failure; Fibroblasts; Fibrosis; Food; Food Supply; Gene Expression; Genetic Transcription; Glucocorticoid Receptor; Half-Life; Health; Heart failure; Hepatic; Hepatotoxicity; Human; Hygiene; In Vitro; Inflammation; Inflammatory; Influenza; Influenza A Virus, H1N1 Subtype; Intake; Kidney; Knowledge; Literature; Lung; Lung diseases; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Measures; Mediating; Metals; Methods; Modeling; Molecular; Molecular Target; Nuclear; Nuclear Proteins; Nuclear Translocation; Occupational Exposure; Oral; Osteoporosis; Oxidation-Reduction; Plants; Policies; Population; Process; Proteins; Proteome; Proteomics; Pulmonary Emphysema; Research; Respiratory physiology; Risk; Risk Assessment; Role; Sampling; Signal Transduction; Source; Stroke; Structure of parenchyma of lung; Sulfhydryl Compounds; System; Techniques; Testing; Thioredoxin; Time; Toxic effect; Transcriptional Regulation; Zinc; base; carcinogenesis; commercial application; drinking water; environmental agent; epidemiologic data; improved; in vivo; inflammatory marker; influenzavirus; knowledge base; link protein; mouse model; nephrotoxicity; oxidation; programs; public health relevance; reproductive; research study; response; transcription factor; transcriptomics; uptake

DESCRIPTION (provided by applicant): Cytoplasmic-nuclear redox signaling: Disruption by dietary cadmium levels Our recent research on the redox dependence of the cysteine proteome shows that levels of cadmium (Cd) present in the American diet stimulate translocation of thioredoxin-1 (Trx1) into cell nuclei and potentiate inflammatory signaling by NF-?B. These levels are below recognized toxic levels and so the results must be approached with caution. None-the-less, the finding has substantial health implications because inflammation contributes to many chronic diseases. Epidemiologic studies associate low-level environmental Cd to the risk of lung cancer, emphysema and other lung diseases, as well as heart failure and stroke, osteoporosis, anemia, reproductive failure and other cancers; poor mechanistic understanding of low-level Cd and confounding variables limit use of these findings in risk assessment or policy decisions. The purpose of this basic science project is to improve mechanistic understanding by testing the central hypothesis that dietary Cd levels potentiate inflammatory lung disease through disruption of the redox proteome associated with actin cytoskeleton control and nuclear function. The project is based upon recent advances in redox-sensitive cytoplasmic-nuclear signaling, our recent data on redox proteomics of low-dose Cd and an extensive literature on biologic effects of Cd. We will use molecular and cellular methods along with mass spectrometry-based redox proteomics to study Cd disruption of cytoplasmic-nuclear redox systems in in vitro and in vivo lung disease models. We specifically focus on the lung because of the central role of redox-sensitive transcription in lung function, especially inflammation and fibrosis, and because dietary Cd effects can be exacerbated by Cd inhalation. Aim 1 is to investigate mechanisms of low-dose Cd on the redox proteome. We will test the hypothesis that Cd effect on actin cytoskeleton proteins causes translocation of Trx1 into nuclei and stimulates activity of transcription factors regulating inflammation and fibrotic responses. Aim 2 is to determine whether low-dose Cd potentiates profibrosis and proinflammation mechanisms by affecting nuclear redox signaling. Studies will use in vitro cell models of pulmonary diseases using bleomycin and H1N1 influenza virus for profibroitc and inflammatory agents, respectively. Aim 3 uses mouse models of pulmonary disease paralleling Aim 2, to test whether low-dose Cd potentiates inflammatory and fibrotic signaling by affecting nuclear redox control systems and transcription factor activity in vivo; the Aim also includes studies of human lung samples to allow direct calibration of model systems to human lung Cd contents. These results will show whether Cd exposures at levels found in the American diet adversely impacts the mechanisms of cytoplasmic-nuclear cell signaling of inflammation and fibrosis. If so, the global proteomic and transcriptomic data, along with calibrated Cd-dependence of markers of inflammation and fibrosis, will provide essential data for targeted evaluation of dietary Cd health risks in humans.

描述（由申请人提供）：细胞质-核氧化还原信号传导：膳食镉水平的干扰我们最近对半胱氨酸蛋白质组的氧化还原依赖性的研究表明，美国饮食中存在的镉（Cd）水平刺激硫氧还蛋白-1（Trx1）易位到细胞核中，并增强 NF-κB 的炎症信号传导。这些水平低于公认的毒性水平，因此必须谨慎对待结果。尽管如此，这一发现对健康具有重大影响，因为炎症会导致许多慢性疾病。流行病学研究将低水平的环境镉与肺癌、肺气肿和其他肺部疾病，以及心力衰竭和中风、骨质疏松症、贫血、生殖障碍和其他癌症的风险联系起来；对低水平镉和混杂变量的机制了解不足，限制了这些发现在风险评估或政策决策中的使用。该基础科学项目的目的是通过测试以下中心假设来提高对机制的理解：饮食中的镉水平通过破坏与肌动蛋白细胞骨架控制和核功能相关的氧化还原蛋白质组来加剧炎症性肺病。该项目基于氧化还原敏感的细胞质核信号传导的最新进展、我们关于低剂量镉氧化还原蛋白质组学的最新数据以及关于镉生物效应的大量文献。我们将使用分子和细胞方法以及基于质谱的氧化还原蛋白质组学来研究体外和体内肺部疾病模型中细胞质-核氧化还原系统的镉破坏。我们特别关注肺，因为氧化还原敏感转录在肺功能（尤其是炎症和纤维化）中发挥着核心作用，而且吸入镉会加剧饮食中镉的影响。目标 1 是研究低剂量 Cd 对氧化还原蛋白质组的作用机制。我们将测试以下假设：Cd 对肌动蛋白细胞骨架蛋白的影响导致 Trx1 易位到细胞核中，并刺激调节炎症和纤维化反应的转录因子的活性。目标 2 是确定低剂量 Cd 是否通过影响核氧化还原信号传导来增强促纤维化和促炎症机制。研究将使用肺部疾病的体外细胞模型，分别使用博莱霉素和 H1N1 流感病毒作为促纤维化剂和炎症剂。目标 3 使用与目标 2 平行的肺部疾病小鼠模型，测试低剂量 Cd 是否通过影响体内核氧化还原控制系统和转录因子活性来增强炎症和纤维化信号传导；该目标还包括对人类肺部样本的研究，以允许 模型系统对人肺镉含量的直接校准。这些结果将表明美国饮食中的镉暴露水平是否会对炎症和纤维化的细胞质-核细胞信号传导机制产生不利影响。如果是这样，全球蛋白质组学和转录组学数据，以及校准的炎症和纤维化标志物的镉依赖性，将为有针对性地评估人类膳食镉健康风险提供重要数据。