EGR-1: Regulator of apoptosis and inflammation in COPD

描述（由申请人提供）：我们阐明人COPD发病机制中涉及的关键途径的方法是从COPD患者人肺组织中调控基因的综合研究中鉴定候选基因。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COPD（GOLD 2）患者与无气流阻塞的吸烟者相比的人类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节的许多重要基因中，我们选择专注于早期生长反应-1（Egr-1）。关注Egr-1的基本原理是基于几个关键因素，包括：1）EGR-1不仅是COPD组织中显著调控的327个基因之一，而且在我们的SAGE分析中验证和确认的基因中位于序列标签命中的顶部; 2）Egr-1调节在目前控制COPD的已建立的途径和范例中至关重要的关键效应分子，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，并将测试Egr-1调节的血红素加氧酶（HO）-1有助于平衡细胞凋亡和炎症过程以实现病理生理学疾病（如COPD）的稳态的假设。因此，我们将通过解决以下具体目标来测试我们的假设：具体目标1。测试Egr-1可以调节细胞凋亡的假设，内在和外在的凋亡途径，香烟烟雾在体外和体内。具体目标2。在体外和体内测试Egr-1可以调节香烟烟雾暴露后的炎症过程，包括趋化因子和细胞因子表达的假设。具体目标3。检验Egr-1调节HO-1表达可以提供有效的抗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。项目叙述。香烟烟雾诱导COPD的分子基础知之甚少。我们将尝试研究在COPD发病机制中起关键作用的特定分子通路。这些途径将在未来潜在地针对COPD患者的治疗的新的治疗方式。

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.