Role of ZIP8 in secondary cigarette smoke exposure-mediated lung injury

ZIP8 在继发性香烟烟雾暴露介导的肺损伤中的作用

基本信息

批准号：
9397646
负责人：
DAREN Lee KNOELL
金额：
$ 19.49万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-15 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9397646
关键词：
Role ZIP8 secondary cigarette smoke

项目摘要

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-κB), 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（由适用提供）：烟烟（CS）暴露是发展慢性阻塞性肺疾病（COPD）的最重要危险因素，这是美国男性和女性发病率和死亡率的主要原因。重要的是，与CS相关的肺部疾病的发病机理尚不清楚，从而造成了改善治疗策略的主要障碍。镉（CD）是香烟烟雾的主要组成部分，也是领先的环境毒物，其生物半衰期超过20年。 CD显着有助于CS诱导的肺部疾病，但尚不清楚CD如何进入肺部或如何介导病理表现。该项目的长期目标是确定人锌转运蛋白，Zip8，锌和CD的转运蛋白，锌和CD的转运蛋白，在第一手（FHS的情况下）在肺部病原体中（FHS）中的肺病原体。我们的中心假设是，由CS暴露驱动的炎症将诱导肺上皮中Zip8的表达，从而增加CD进入，免疫功能障碍和肺病理学。该假设是基于我们小组的最新发布和初步观察结果，证明Zip8的表达在肺上皮中并非自然丰富，由NFKappab（NF-κB）上调，NFKappab（NF-κB）是一种由CS暴露激活的关键信号通路，并通过CS的表达增加了Zip8表达的表达，增强了Lung Eptake cd unpate cd的范围。我们方法的理由是，在CS暴露，免疫激活和饮食锌摄入量的背景下，建立ZIP8在肺微环境中的功能作用将提高我们对CS相关的肺部疾病的理解，并促进创新的微生物监测和治疗策略。在强有力的初步证据的指导下，将通过追求两个具体目的来检验：1）评估FHS暴露对BTZIP8过表达小鼠（与野生型匹配的对照组相比）相对于BTZIP8中ZIP8的氧化状态和免疫功能障碍的影响； 2）确定锌营养在体内的影响是ROS形成，免疫功能障碍和长时间FHS暴露后的肺损伤的诱发因素。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，以探讨Zip8，氧化还原状态，免疫功能障碍和体内锌营养的作用。本应用程序中提出的研究具有创新性，因为它将首次批判性地评估锌代谢在与CS相关病原体的环境中的作用。这很重要，因为它将定义一种调节氧化还原和免疫功能的新型途径的功能意义，从而揭示了对与CS相关的肺部疾病的新分子见解，这将导致创新的策略，以防止或更好地治疗这种致命的疾病