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EGR-1: Regulator of apoptosis and inflammation in COPD

EGR-1：COPD 细胞凋亡和炎症的调节因子

基本信息

批准号：
7464660
负责人：
Augustine M Choi
金额：
$ 50.07万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7464660
关键词：
Address Adenoviruses Affect Age Air Alveolar Macrophages Animals Annexins Anti-Inflammatory Agents Anti-inflammatory Antibodies Antioxidants Apoptosis Apoptosis Inhibitor Apoptosis Regulator Apoptotic Attenuated BIRC4 gene Bile Acids Binding Sites Biological Biological Assay Biological Process Candidate Disease Gene Caspase Cell Death Cell Line Cell Proliferation Cell Separation Cells Cellular Stress Cessation of life Chemicals Chronic Chronic Obstructive Airway Disease Cigarette Collaborations Complement Complex Core Facility Critical Pathways Cytochromes Cytoprotection DNA DNA Binding Data Development Dinucleoside Phosphates Disease Dominant-Negative Mutation Dose Doxycycline Economic Inflation Elastases Electrophoretic Mobility Shift Assay Ensure Epithelial Epithelial Cells Epithelium Equilibrium European Event Excision Exhibits Family member Fibroblasts Funding Future Gene Activation Gene Expression Gene Expression Profiling Gene Expression Regulation Gene Proteins Gene Transfer Genes Genetic Polymorphism Genetic Transcription Gold Grant Growth Heme Histologic Homeostasis Human Hyperplasia Immunoblotting Immunoprecipitation In Situ Nick-End Labeling In Vitro Individual Inflammation Inflammatory Injection of therapeutic agent Injury Intercept Japanese Population Kinetics Knock-in Mouse Knockout Mice Label Laboratories Laboratory mice Letters Life Ligands Liposomes Luciferases Lung Lymphatic Diseases Measurable Measurement Measures Mediating Metalloporphyrins Methods Microarray Analysis Microscopy Mitochondria Modality Modeling Molecular Molecular Profiling Mouse Strains Mus Mutate Nuclear Nuclear Extract Obstruction Oligonucleotide Probes Oxidants Oxidative Stress Oxygenases Pathogenesis Pathway interactions Patients Pattern Peptide Hydrolases Phenotype Phosphorylation Play Process Production Proteins Protocols documentation Publishing Pulmonary Emphysema RNA RNA Interference Reagent Regulation of Apoptosis Pathway Relative (related person)Reporter Reporting Research Research Design Resort Response Elements Reverse Transcriptase Polymerase Chain Reaction Rodent Role Slide Small Interfering RNA Smoker Specificity Staining method Stains Stress Structure of parenchyma of lung System TdT-Mediated dUTP Nick End Labeling Assay Techniques Testing Tetanus Helper Peptide Time Tissue Preservation Tissue-Specific Gene Expression Tissues Tobacco Tobacco smoke Transfection Transgenic Mice Universities Western Blotting Work animal colony annexin A5 attenuation base biological adaptation to stress caspase-3 caspase-8 caspase-9 cell type cellular imaging chemokine cigarette smoke-induced cigarette smoking cohort cytochrome c cytokine experience gain of function heme oxygenase-1 immune function improved in vitro Model in vivo in vivo Model inhibitor/antagonist insight loss of function mutant new therapeutic target overexpression oxidant stress promoter protein expression receptor research study response satisfaction success tobacco exposure vector

项目摘要

DESCRIPTION (provided by applicant): Our approach in elucidating critical pathways involved in the pathogenesis of human COPD has been to identify candidate genes from a comprehensive study of regulated genes in human lung tissues of individuals with COPD. We performed comprehensive gene expression profiling by means of SAGE and microarray analysis to examine differential gene expression patterns and identify candidate genes in human lung tissues of individuals with COPD (GOLD 2) compared with that of smokers without airflow obstruction. Among the many significant genes markedly regulated in our analysis, we have chosen to focus on early growth response-1 (Egr-1). The rationale for focusing on Egr-1 is based on several critical factors including: 1) EGR-1 was not only one of the 327 expressed genes significantly regulated in COPD tissues, but also ranked at the top of sequences tag hits among the genes we validated and confirmed in our SAGE analysis; 2) Egr-1 regulates key effector molecules critical in the established pathways and paradigms currently governing COPD including apoptosis, inflammation, oxidant/antioxidant balance, proteases/anti-proteases, and immune functions; 3) Our in vitro and in vivo preliminary studies demonstrate that cigarette smoke in both in vivo and in vitro regulate Egr-1 expression. We will use both in vitro and in vivo models to test the hypothesis that Egr-1 acts as a critical upstream master switch molecule in regulating apoptosis and inflammation in COPD. We will also examine how Egr-1 regulates adaptive and stress responses to defend against the apoptotic and inflammatory processes, and will test the hypothesis that Egr-1 regulated heme oxygenase (HO)-1 helps counter balance against the apoptotic and inflammatory processes to achieve homeostasis in pathophysiologic disorders such as COPD Hence, we will test our hypothesis by addressing the following specific aims: Specific Aim 1. Test the hypothesis that Egr-1 can regulate apoptosis, both intrinsic and extrinsic apoptotic pathways, following cigarette smoke in vitro and in vivo. Specific Aim 2. Test the hypothesis that Egr-1 can regulate inflammatory process, both chemokine and cytokine expression, following cigarette smoke exposure in vitro and in vivo. Specific Aim 3. Test the hypothesis that Egr-1 regulated HO-1 expression can provide potent anti-apoptotic and anti-inflammatory effects, critical in the adaptive and stress response of cytoprotection against cigarette smoke. PROJECT NARRATIVE. The molecular basis of cigarette smoke induced COPD is poorly understood. We will attempt to examine specific molecular pathways which plays critical role in the pathogenesis of COPD. These pathways will potentially target new therapeutic modality in the future for the treatment of patients with COPD.

描述（由申请人提供）：我们阐明人类慢性阻塞性肺病发病机制中涉及的关键途径的方法是从对患有慢性阻塞性肺病的个体的人类肺组织中的调节基因的综合研究中确定候选基因。我们通过 SAGE 和微阵列分析进行了全面的基因表达谱分析，以检查差异基因表达模式，并与没有气流阻塞的吸烟者相比，识别 COPD (GOLD 2) 个体的人肺组织中的候选基因。在我们的分析中受到显着调控的许多重要基因中，我们选择关注早期生长反应-1 (Egr-1)。关注 Egr-1 的理由基于几个关键因素，包括：1）EGR-1 不仅是 COPD 组织中显着调控的 327 个表达基因之一，而且在我们在 SAGE 分析中验证和确认的基因中排名在序列标签命中的顶部； 2) Egr-1调节关键效应分子，这些分子在目前控制COPD的既定途径和范式中至关重要，包括细胞凋亡、炎症、氧化剂/抗氧化剂平衡、蛋白酶/抗蛋白酶和免疫功能； 3）我们的体外和体内初步研究表明，香烟烟雾在体内和体外均调节Egr-1的表达。我们将使用体外和体内模型来检验 Egr-1 作为调节 COPD 细胞凋亡和炎症的关键上游主开关分子的假设。我们还将研究 Egr-1 如何调节适应性和应激反应以防御细胞凋亡和炎症过程，并将检验 Egr-1 调节血红素加氧酶 (HO)-1 有助于平衡细胞凋亡和炎症过程以实现慢性阻塞性肺病等病理生理疾病的体内平衡的假设。因此，我们将通过解决以下具体目标来检验我们的假设：具体目标 1. 检验假设 Egr-1 可以在体外和体内香烟烟雾后调节细胞凋亡，包括内在和外在的细胞凋亡途径。具体目标 2. 测试以下假设：在体外和体内暴露于香烟烟雾后，Egr-1 可以调节炎症过程，包括趋化因子和细胞因子的表达。具体目标 3. 检验以下假设：Egr-1 调节 HO-1 表达可以提供有效的抗凋亡和抗炎作用，这对于针对香烟烟雾的细胞保护的适应性和应激反应至关重要。项目叙述。香烟烟雾诱发慢性阻塞性肺病的分子基础尚不清楚。我们将尝试检查在 COPD 发病机制中起关键作用的特定分子途径。这些途径可能会在未来针对慢性阻塞性肺病患者的治疗提供新的治疗方式。