EGR-1: Regulator of apoptosis and inflammation in COPD

EGR-1：COPD 细胞凋亡和炎症的调节因子

• 批准号: 7851060
• 负责人: Augustine M Choi
• 金额: $ 53.4万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 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/7851060
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Apoptosis Regulator; Apoptotic; Biological Process; Candidate Disease Gene; Chronic Obstructive Airway Disease; Critical Pathways; Cytoprotection; Data; Disease; Equilibrium; Future; Gene Expression Profiling; Genes; Gold; Growth; Heme; Homeostasis; Human; In Vitro; Individual; Inflammation; Inflammatory; Literature; Microarray Analysis; Modality; Molecular; Molecular Profiling; Obstruction; Oxidants; Oxygenases; Pathogenesis; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Play; Process; Publishing; Regulation; Research; Role; Smoker; Stress; Structure of parenchyma of lung; Testing; Tissue-Specific Gene Expression; Tissues; base; biological adaptation to stress; chemokine; cigarette smoke-induced; cigarette smoking; cytokine; heme oxygenase-1; immune function; in vivo; in vivo Model; insight; new therapeutic target; response

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(申请人提供)：我们在阐明涉及人类COPD发病机制的关键途径方面的方法是从COPD患者的人类肺组织中调节基因的综合研究中识别候选基因。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COPD患者(GOLD-2)和没有气流障碍的吸烟者肺组织中的差异基因表达模式，并确定候选基因。在我们的分析中显著调控的许多重要基因中，我们选择了关注早期生长反应-1(Egr-1)。我们之所以关注Egr-1，是基于一些关键因素，包括：1)EGR-1不仅是我们在SAGE分析中确认和确认的基因中最受调控的327个表达基因之一，而且在我们的SAGE分析中被列为序列标签命中的顶部；2)Egr-1调控在目前已建立的调控COPD的途径和范式中至关重要的关键效应分子，包括细胞凋亡、炎症、氧化/抗氧化平衡、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，体内和体外的香烟烟雾都调节Egr-1的表达。我们将使用体外和体内模型来验证这一假设，即Egr-1在COPD中作为关键的上游主开关分子调控细胞凋亡和炎症。我们还将研究Egr-1如何调节适应性和应激反应以抵御凋亡和炎症过程，并将检验Egr-1调控的血红素加氧酶(HO)-1有助于平衡细胞凋亡和炎症过程以实现COPD等病理生理障碍的动态平衡的假设。因此，我们将通过解决以下特定目标来验证我们的假设：特定目标1.在体外和体内测试Egr-1可以调节香烟烟雾后细胞凋亡的假设，包括内在和外在的凋亡途径。特定目的2.在体内外验证Egr-1可调节香烟烟雾暴露后炎症过程的假设，包括趋化因子和细胞因子的表达。特定目的3.验证Egr-1调控的HO-1表达可以提供强大的抗细胞凋亡和抗炎作用的假设，这在香烟烟雾的细胞保护的适应性和应激反应中至关重要。项目叙事。吸烟导致慢性阻塞性肺疾病的分子基础尚不清楚。我们将尝试研究在COPD发病机制中起关键作用的特定分子途径。这些途径可能在未来针对COPD患者的治疗新的治疗方式。