Targeting Oxidative Stress in Chronic Beryllium Disease

针对慢性铍病的氧化应激

基本信息

批准号：
8246509
负责人：
Brian J Day
金额：
$ 33.99万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8246509
关键词：
Acetylation Address Anti-Inflammatory Agents Anti-inflammatory Antigens Antioxidants Beryllium Biochemical Bronchoalveolar Lavage CD4 Positive T Lymphocytes Cell Proliferation Cells Chronic Chronic berylliosis Clinical Research Couples Cysteine DNA Double-Blind Method Drug usage Equilibrium Flow Cytometry Functional disorder Glucocorticoid Receptor Goals Granuloma Granulomatous HDAC2 gene Heat shock proteins Histones Homeostasis Human Hypersensitivity Immune response In Vitro Inflammation Inflammatory Interferons Interleukin-2 Lipids Lung Lung Inflammation Lung diseases Mediating Mesalamine Modification Molecular Normal Cell Oxidation-Reduction Oxidative Stress Pathogenesis Pathway interactions Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phosphorylation Population Prednisone Production Proliferating Property Proteins Randomized Recycling Respiratory physiology Role Salicylic Acids Spirometry Steroids Sulfhydryl Compounds T cell response T-Cell Proliferation T-Lymphocyte TNF gene Testing Therapeutic Effect Thioredoxin Ubiquitination Ulcerative Colitis base capsule cell type cytokine histone acetyltransferase in vivo macrophage nitration novel novel strategies novel therapeutic intervention oxidation placebo controlled study public health relevance pulmonary granuloma research study response secondary outcome stress protein therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this application is to understand the role of oxidative stress as a potential target in the pathogenesis of chronic beryllium disease (CBD). CBD is an inflammatory hypersensitivity lung disease that occurs in over 800,000 beryllium-exposed workers in the US characterized by pulmonary granulomas. The molecular mechanisms by which beryllium regulates the chronic production of lung inflammation and granuloma formation are unknown. We hypothesize that beryllium induces oxidative stress by altering thiol homeostasis which enhances beryllium specific T cells to produce excessive Th1 cytokines and proliferate, two key features of CBD pathophysiology. Three specific aims are proposed to address the hypothesis. Specific aim 1 will examine the mechanisms by which beryllium stimulates oxidative stress in beryllium specific CD4+ T cells by altering thiol redox status. Specific aim 2 will determine whether beryllium-mediated oxidative stress alters the balance between histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) activities that modulates inflammation and steroid sensitivity in CBD. This aim will test whether beryllium exposure creates oxidative stress that impairs HDAC activity as a mechanism that amplifies inflammation in CBD. Specific aim 3 will examine the potential therapeutic effect of a 5 aminosalicylic acid in CBD subjects. This last aim will assess a novel new therapy in CBD patients that targets beryllium-mediated oxidative stress and inflammation. The proposed experiments elucidate novel mechanisms that explain the excessive cytokine response to beryllium and pinpoint the role of antioxidant imbalance in CBD and mechanistic approaches to treat CBD. PUBLIC HEALTH RELEVANCE: CBD is a granulomatous lung disease that occurs in a large population of US workers exposed to beryllium. The proposed study focuses on novel findings that beryllium is both an antigen and initiator of oxidative stress that results in alterations in cellular thiol status. The studies will mechanistically target these changes with a novel therapeutic approach using 5 aminosalicylic acid in CBD subjects.

描述（由申请人提供）：本申请的总体目标是了解氧化应激作为慢性铍病（CBD）发病机制中潜在目标的作用。 CBD 是一种炎症性超敏性肺部疾病，在美国有超过 800,000 名接触铍的工人发生，其特征是肺肉芽肿。铍调节肺部炎症和肉芽肿形成的慢性产生的分子机制尚不清楚。我们假设铍通过改变硫醇稳态来诱导氧化应激，从而增强铍特异性 T 细胞产生过量的 Th1 细胞因子并增殖，这是 CBD 病理生理学的两个关键特征。提出了三个具体目标来解决这一假设。具体目标 1 将研究铍通过改变硫醇氧化还原状态刺激铍特异性 CD4+ T 细胞氧化应激的机制。具体目标 2 将确定铍介导的氧化应激是否会改变组蛋白乙酰转移酶 (HAT) 和组蛋白脱乙酰转移酶 (HDAC) 活性之间的平衡，从而调节 CBD 中的炎症和类固醇敏感性。这一目标将测试铍暴露是否会产生氧化应激，从而损害 HDAC 活性，作为放大 CBD 炎症的机制。具体目标 3 将检查 5 个氨基水杨酸对 CBD 受试者的潜在治疗效果。最后一个目标将评估一种针对 CBD 患者的新型疗法，该疗法针对铍介导的氧化应激和炎症。拟议的实验阐明了新的机制，解释了对铍的过度细胞因子反应，并查明了 CBD 中抗氧化剂失衡的作用以及治疗 CBD 的机制方法。公共卫生相关性：CBD 是一种肉芽肿性肺部疾病，发生在大量接触铍的美国工人中。拟议的研究重点关注铍既是抗原又是氧化应激引发剂的新发现，氧化应激会导致细胞硫醇状态的改变。这些研究将通过在 CBD 受试者中使用 5 个氨基水杨酸的新型治疗方法从机制上针对这些变化。