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

基本信息

批准号：
9265855
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
项目类别：
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/9265855
关键词：
Actins Acute Affect Alveolar American diet 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 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 Pathogenicity 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 TXN gene Techniques Testing Time Toxic effect Transcriptional Regulation Zinc base carcinogenesis commercial application drinking water environmental agent epidemiologic data epidemiology study experimental study human disease improved in vivo inflammatory lung disease inflammatory marker influenzavirus knowledge base link protein mouse model nephrotoxicity oxidation programs public health relevance reproductive response transcription factor transcriptomics uptake

项目摘要

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-κB. 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（申请人证明）：细胞质核氧化还原信号：饮食中的钙蛋白酶蛋白质组的氧化还原均受到饮食中的氧化还原。（TRX1）进入细胞核和NF-κB的炎症信号传导。。 CD水平通过破坏氧化还原蛋白质组的炎症肺部与肌肉骨骼控制和核功能相关。。特别是纤维化和纤维化核心信号传导分别是炎症剂3还包括对人类肺样本的研究将模型系统直接校准了人类肺CD含量。人类炎症isk的炎症的CD否定性。