Role of p73 in COPD Pathogenesis

项目总结 慢性阻塞性肺疾病(COPD)是美国第四大死因， 无法治愈。虽然慢性烟草烟雾暴露与慢性阻塞性肺病之间的联系已被认为是 几十年来，慢性阻塞性肺疾病戒烟后持续肺损伤的原因仍不清楚。我们和 另一些研究表明，随着多纤毛细胞(MCC)的丢失，上皮重塑在 慢性阻塞性肺疾病患者的呼吸道和个别小气道上皮细胞分化异常 与分泌性IgA(SIgA)屏障的丧失、慢性炎症和纤维组织重塑有关 气道壁。此外，我们还表明，呼吸道中sIgA的丢失足以诱导COPD样表型。 在小鼠中，这表明粘膜免疫改变在COPD的发病机制中起着因果作用。在这项提案中，我们 将专注于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，最近显示的分化因子p73 是MCC发育所必需的，是MCC特异性表达所必需的运输蛋白 用于SIgA跨细胞反应(聚合免疫球蛋白受体或pIgR)。我们发现香烟烟雾能抑制 P73在体外和体内的表达，提供了香烟烟雾暴露之间的机制联系，异常 上皮分化，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MCC丢失，pIgR表达和SIgA减少 细胞穿透，免疫屏障功能受损。在目标1中，我们将调查定向删除的影响 P73或pIgR在表达FoxJ1的多纤毛细胞中对呼吸道上皮细胞分化和免疫防御的影响 在目标2中，我们将确定p73依赖的转录因子来调节小鼠气管上皮中的pIgR。 细胞，并在原代人支气管上皮细胞中验证我们的发现。在目标3中，我们将定义 体内吸烟、p73表达与上皮分化的关系。加在一起，这些 研究将确定正常上皮分化缺陷如何导致粘膜免疫功能改变。 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.