Epithelial GILZ in Inflammation and Remodeling

项目总结(见说明)： 持续性哮喘常伴有呼吸道重塑，占哮喘发病率和死亡率的不成比例比例。该上皮细胞被认为在与鼻病毒诱导的哮喘加重和糖皮质激素抵抗有关的呼吸道重塑中起着不可或缺的作用。糖皮质激素诱导的亮氨酸拉链(GILZ)是一种多能的内源性抗炎蛋白，可抑制NF-KB、AP-1和MAPK信号转导，在哮喘上皮细胞中被抑制。总体假设是，哮喘重塑的程度受到气道上皮细胞GILZ表达的强烈影响，即使在糖皮质激素抵抗的哮喘患者中，增加GILZ的治疗策略也可能阻止重塑。提出了三个目标：目标1将解决GILZ表达减少是否会导致更严重的哮喘恶化和气道重塑；目标2将解决糖皮质激素抵抗是否与糖皮质激素未能反式激活GILZ mRNA表达有关；以及目标3将解决是否通过非糖皮质激素机制增加GILZ的治疗策略是否能减少气道炎症并保护患者免受哮喘加重和气道重塑的影响。拟议的工作将大量利用哮喘临床核心中心的人类哮喘受试者。该方法将首先分析哮喘(或正常)受试者的原代支气管上皮细胞，这些受试者受到相关过敏原或鼻病毒的攻击，或者哮喘受试者对糖皮质激素耐药(或敏感)，然后使用正常的人类呼吸道上皮细胞寻求机械延伸，最后是一种独特的小鼠品系，在该品系中，GILZ已从呼吸道上皮细胞中遗传缺失。GILZ是一种抗炎蛋白，这些实验的数据将补充该计划项目中其他两个项目中相同样本的促炎数据。在这些研究结束时，将确定GILZ作为变态反应性气道炎症调节剂的重要性，并确定其在糖皮质激素抵抗中的作用。将评估增加呼吸道上皮细胞GILZ的非基于糖皮质激素的方法的治疗潜力，并提供该项目最重要的长期目标。

PROJECT SUMMARY (See instructions): Persistent asthma is often accompanied by airway remodeling that accounts for a disproportionate fraction of asthma morbidity and mortality. The epithelium is thought to play an integral role in airway remodeling linked to rhinovirus-induced asthma exacerbations and glucocorticoid resistance. Glucocorticoid-induced leucine zipper (GILZ) is a pluripotent endogenous anti-inflammatory protein that inhibits NF-KB, AP-1 and MAPK signaling and that is reduced in asthmatic epithelial cells. The overall hypothesis is that the extent of asthmatic remodeling is strongly influenced by the expression of GILZ in airway epithelial cells, and that therapeutic strategies to increase GILZ may prevent remodeling even in asthmatic patients with glucocorticoid resistance. Three aims are proposed: Aim #1 will address whether decreased expression of GILZ contribute to more severe asthma exacerbations and airway remodeling; Aim #2 will address whether glucocorticoid resistance involves a failure of glucocorticoids to trans-activate GILZ mRNA expression; and Aim #3 will address whether therapeutic strategies to increase GILZ via a non-glucocorticoid mechanism decrease airway inflammation and protect patients from asthma exacerbations and airway remodeling. The proposed work will heavily utilize human asthmatic subjects from the Asthma Clinical Core. The approach will start with the analysis of primary bronchial epithelial cells from either asthmatic (or normal) subjects who are challenged with relevant allergen or rhinovirus or asthmatic subjects who are glucocorticoid resistant (or sensitive), then seek mechanistic extensions using normal human airway epithelial cells and finally a unique mouse strain in which GILZ has been genetically deleted from airway epithelial cells. GILZ is an anti-inflammatory protein, and the data from these experiments will complement the pro-inflammatory data from the same samples in the other two projects in this program project. By the end of these studies, the importance of GILZ as rheostat for allergic airway inflammation will be defined, and its role in glucocorticoid resistance defined. The therapeutic potential of non-glucocorticoid based approaches to increase GILZ in airway epithelial cells will be assessed and provides the most important long-term goal of the project.