Role of ZIP8 in first hand cigarette smoke exposure-mediated lung injury

ZIP8 在第一手香烟烟雾暴露介导的肺损伤中的作用

• 批准号: 8630038
• 负责人: DAREN Lee KNOELL
• 金额: $ 39.85万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630038
• 关键词: Alveolar Macrophages; Animal Model; Biological; Cadmium; Chronic; Chronic Obstructive Airway Disease; Cigarette; Data; Development; Dietary Zinc; Disease; Epidemiology; Epithelium; Equilibrium; Fostering; Goals; Half-Life; Health; Human; Immune System Diseases; Inflammation; Inflammatory; Injury; Intake; Investigation; Knowledge; Lead; Lung; Lung diseases; Mediating; Metabolism; Micronutrients; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Oxidants; Oxidation-Reduction; Pathogenesis; Pathology; Pathway interactions; Pilot Projects; Play; Predisposing Factor; Preventive; Public Health; Publishing; Relative (related person); Research; Risk; Risk Factors; Role; Signal Pathway; Smoke; Smoker; Testing; Time; Toxic Environmental Substances; Toxic effect; United States; Woman; Work; Zinc; Zinc deficiency; base; cigarette smoke-induced; cigarette smoking; disability; effective therapy; immune activation; immune function; improved; in vivo; innovation; insight; lung injury; macrophage; men; mortality; non-smoker; novel; nutrition; overexpression; prevent; surveillance strategy; treatment strategy; uptake; zinc-binding protein

DESCRIPTION (provided by applicant): Cigarette smoke (CS) exposure is the most important risk factor for developing chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality in men and women in the United States. Importantly, the pathogenesis of CS-related lung disease remains unclear thereby creating a major obstacle to generate improved treatment strategies. Cadmium (Cd) is a major component of cigarette smoke and a leading environmental toxicant with a biological half-life of greater than 20 years. Cd significanty contributes to CS- induced lung disease but it is not known exactly how Cd enters the lung or how it mediates pathological manifestations once in. The long-term goal of this project is to determine the role of the human zinc transporter, ZIP8, a transporter of both zinc and Cd, in lung pathogenesis in the context of first hand (FHS) smoke exposure. Our central hypothesis is that inflammation driven by CS exposure will induce the expression of ZIP8 in lung epithelia thereby increasing Cd entry, immune dysfunction, and lung pathology. This hypothesis is predicated on recent published and preliminary observations by our group demonstrating that ZIP8 expression, not naturally abundant in lung epithelia, is up-regulated by NFkappaB (NF-?B), a key signaling pathway that is activated by CS exposure, and that increased ZIP8 expression enhances Cd uptake into lung epithelia which is further enhanced by zinc deficiency. The rationale for our approach is that establishment of the functional role of ZIP8 within the lung microenvironment in the context of CS exposure, immune activation, and dietary zinc intake, will improve our understanding of CS-related lung disease and foster innovative micronutrient surveillance and treatment strategies. Guided by strong preliminary evidence, this hypothesis will be tested by pursuing two specific aims that: 1) Evaluate the effects of FHS exposure on oxidative status and immune dysfunction in vivo relative to ZIP8 in BTZIP8 overexpressing mice (compared to wild-type matched controls); and 2) Determine the impact of zinc nutrition in vivo as a predisposing factor in ROS formation, immune dysfunction, and lung damage following prolonged FHS exposure. To accomplish the goals of aim 1 and 2 we will pursue novel studies in animal models that explore the role of ZIP8, redox status, immune dysfunction, and zinc nutrition in vivo. The research proposed in this application is innovative because it will for the first time critically evaluate the role of zinc metabolism in the setting of CS-related pathogenesi. This is important because it will define the functional significance of a novel pathway that regulates redox and immune function thereby revealing new molecular insight into CS-related lung disease that will lead to innovative strategies to prevent or better treat this lethal disease

描述（由申请人提供）：香烟烟雾（CS）暴露是发生慢性阻塞性肺疾病（COPD）的最重要风险因素，COPD是美国男性和女性发病率和死亡率的主要原因。重要的是，CS相关肺部疾病的发病机制仍不清楚，从而产生一个主要障碍，以产生改进的治疗策略。镉（Cd）是香烟烟雾的主要成分，也是一种主要的环境毒物，生物半衰期超过20年。Cd显著促进CS诱导的肺部疾病，但尚不清楚Cd如何进入肺部或其如何介导病理表现。该项目的长期目标是确定人类锌转运蛋白ZIP 8（锌和镉的转运蛋白）在第一手（FHS）烟雾暴露背景下肺发病机制中的作用。我们的中心假设是CS暴露驱动的炎症将诱导肺上皮中ZIP 8的表达，从而增加Cd进入、免疫功能障碍和肺病理学。这一假设是基于我们小组最近发表的初步观察结果，表明ZIP 8的表达，在肺上皮中不是天然丰富的，是由NF κ B（NF-？B），这是一种被CS暴露激活的关键信号传导途径，并且增加的ZIP 8表达增强了肺上皮对Cd的摄取，这通过锌缺乏进一步增强。我们的方法的基本原理是，在CS暴露，免疫激活和膳食锌摄入的背景下，在肺微环境中建立ZIP 8的功能作用，将提高我们对CS相关肺部疾病的理解，并促进创新的微量营养素监测和治疗策略。在强有力的初步证据的指导下，将通过追求两个具体目标来测试该假设：1）在BTZIP 8过表达小鼠中，相对于ZIP 8，评价FHS暴露对体内氧化状态和免疫功能障碍的影响（与野生型匹配对照相比）;和2）确定体内锌营养作为ROS形成，免疫功能障碍，以及长期暴露于FHS后的肺损伤。为了实现目标1和2的目标，我们将在动物模型中进行新的研究，探索ZIP 8的作用，氧化还原状态，免疫功能障碍和体内锌营养。本申请中提出的研究具有创新性，因为它将首次严格评估锌代谢在CS相关病因中的作用。这是重要的，因为它将定义一种调节氧化还原和免疫功能的新途径的功能意义，从而揭示对CS相关肺部疾病的新分子见解，这将导致预防或更好地治疗这种致命疾病的创新策略