Role of p73 in COPD Pathogenesis

项目摘要 慢性阻塞性肺疾病（COPD）是美国第四大死亡原因， 无法治愈虽然慢性烟草烟雾暴露与COPD之间的关系已经被认为是 几十年来，COPD患者戒烟后持续肺损伤的原因仍不明确。我们和 其他人已经表明，上皮重塑与损失的多纤毛细胞（MCC）是普遍的， COPD患者的气道和个体小气道中的异常上皮分化强烈 与分泌伊加（SIgA）屏障丧失、慢性炎症和纤维化重塑相关 气道壁此外，我们发现气道中SIgA的缺失足以诱导COPD样表型 在小鼠中，表明改变的粘膜免疫在COPD发病机制中起因果作用。在本提案中，我们 将重点放在粘膜免疫屏障功能受损的根本原因，我们认为这是异常的， 上皮分化我们的初步数据表明，分化因子p73，最近显示， 是MCC发育所必需的，是MCC特异性表达所需的转运蛋白所必需的 用于SIgA转胞吞作用（多聚免疫球蛋白受体或pIgR）。我们发现香烟烟雾抑制了 p73在体外和体内的表达，提供了香烟烟雾暴露、异常吸烟和吸烟之间的机制联系。 上皮分化和粘膜免疫屏障功能受损。在本提案中，我们将测试 假设香烟烟雾抑制p73，导致MCCs的损失，减少pIgR表达和SIgA 转胞吞作用和受损的免疫屏障功能。在目标1中，我们将研究靶向缺失的影响 p73或pIgR在表达FoxJ1的多纤毛细胞中对气道上皮分化和免疫防御的影响。 在目标2中，我们将鉴定调节小鼠气管上皮中pIgR的p73依赖性转录因子 细胞，并验证我们在原代人支气管上皮细胞中的发现。在目标3中，我们将定义 香烟烟雾、p73表达和体内上皮分化之间的关系。所有这些 研究将确定正常上皮分化缺陷如何导致粘膜免疫的改变 并评估p73是否代表慢性炎症和MCC丢失之间的机制联系。

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and has no cure. While the association between chronic tobacco smoke exposure and COPD has been known for decades, the reasons for ongoing lung damage in COPD after smoking cessation remain undefined. We and others have shown that epithelial remodeling with loss of multiciliated cells (MCCs) is widespread in the airways of COPD patients and abnormal epithelial differentiation in individual small airways is strongly associated with loss of the secretory IgA (SIgA) barrier, chronic inflammation, and fibrotic remodeling of the airway wall. Further, we showed that loss of SIgA in the airways is sufficient to induce a COPD-like phenotype in mice, suggesting altered mucosal immunity plays a causal role in COPD pathogenesis. In this proposal, we will focus on the underlying cause of impaired mucosal immunobarrier function which we believe to abnormal epithelial differentiation. Our preliminary data demonstrate that the differentiation factor p73, recently shown to be required for the MCC development, is required for MCC-specific expression of a transport protein required for SIgA transcytosis (polymeric immunoglobulin receptor or pIgR). We found that cigarette smoke suppresses p73 expression in vitro and in vivo, providing a mechanistic link between cigarette smoke exposure, abnormal epithelial differentiation, and impaired mucosal immunobarrier function. In this proposal, we will test the hypothesis that cigarette smoke suppresses p73, resulting in loss of MCCs, reduced pIgR expression and SIgA transcytosis, and impaired immunobarrier function. In Aim 1, we will investigate the impact of targeted deletion of p73 or pIgR in FoxJ1-expressing multiciliated cells on airway epithelial differentiation and immune defense. In Aim 2 we will identify p73-dependent transcription factors that regulate pIgR in murine tracheal epithelial cells and validate our findings in primary human bronchial epithelial cells. In Aim 3 we will define the relationships between cigarette smoke, p73 expression, and epithelial differentiation in vivo. Together, these studies will determine how defects in normal epithelial differentiation result in alterations in mucosal immunity and evaluate whether p73 represents a mechanistic link between chronic inflammation and MCC loss.