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：
7749333
负责人：
Brian J Day
金额：
$ 33.64万
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/7749333
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 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 Proliferation T-Lymphocyte 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）：本应用的总体目标是了解氧化应激作为慢性铍病（CBD）发病机理中潜在靶标的作用。 CBD是一种炎症性超敏反应肺疾病，在以肺肉芽肿为特征的美国有80万多个暴露于铍的工人中发生。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细胞产生过多的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该假设。特定的目标1将检查铍特异性CD4+ T细胞中铍刺激氧化应激的机制，通过改变硫醇氧化还原状态。具体的目标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）和组蛋白脱乙酰基转移酶（HDAC）活性之间的平衡，从而调节CBD中炎症和类固醇敏感性。该目的将测试铍暴露是否会产生氧化应激，从而损害HDAC活性，作为扩大CBD炎症的机制。具体目标3将检查5氨基酸氨酸在CBD受试者中的潜在治疗作用。最后一个目标将评估针对铍介导的氧化应激和炎症的CBD患者的新型新疗法。提出的实验阐明了新的机制，这些机制解释了细胞因子对铍的过度反应，并指出了抗氧化剂失衡在CBD中的作用以及治疗CBD的机械方法。公共卫生相关性：CBD是一种肉芽肿性肺部疾病，发生在暴露于铍的美国大量工人中。拟议的研究重点是新发现，即铍既是氧化应激的抗原，又是导致细胞硫醇状况改变的启动。这些研究将通过在CBD受试者中使用5种氨基酸酸的新型治疗方法来机械地靶向这些变化。