Autophagy-mediated mucin degradation is necessary for resolution of mucous metaplasia

包括哮喘、COPD、囊性纤维化和非慢性支气管扩张症在内的粘液阻塞性呼吸道疾病 不同的遗传和环境来源，但具有某些共同特征，包括病理性上皮 这些变化称为粘液化生。用高脚杯将呼吸道分泌细胞分化为粘液细胞 细胞形态中含有粘蛋白颗粒，含有MUC5AC，少量含有MUC5B。这些呼吸道 疾病的特点是由于粘液过度分泌和血管阻塞而频繁加重。 导致肺功能丧失、住院和死亡风险的呼吸道疾病。虽然许多因素都是 由于粘液化生已被发现，但对其如何消退知之甚少。自噬是一把钥匙 细胞蛋白质循环系统，降解蛋白质以应对营养缺乏、炎症和 感染。在过去的几年里，我们一直在用模型研究自噬在呼吸道疾病中的作用。 伴随着一个关键的自噬调控基因的基因缺失。在本申请中，我们提出了一种新的范式 哪种粘蛋白颗粒的降解通过作用于粘液化生而促进粘液化生的消退 自噬。我们初步数据中的三个关键发现支持这一假设：第一，自噬缺陷小鼠 细胞培养模型在粘液化生和非典型增生过程中积累更多的细胞质粘蛋白颗粒。 尤其是在解决问题时。第二，粘膜上皮化生与mTOR激活和增加有关 上皮代谢，然后在分解过程中被下调。我们认为，这种新陈代谢的转变是 关键触发在分解过程中启动粘蛋白降解。第三，模仿新陈代谢的这种转变 MTOR抑制剂导致人呼吸道上皮细胞分泌自噬激活和粘蛋白降解 细胞。 为了验证自噬导致粘蛋白颗粒降解的假设，我们提出了三项研究。 目的：首先，我们将确定mTOR信号如何在分泌细胞和 最终导致自噬介导的粘蛋白降解。第二，我们将描述 自溶酶体-溶酶体融合在粘液化生消退中的应用 生物发生和溶酶体蛋白分解功能。第三，我们将探索粘蛋白降解作为一种治疗方法 黏膜阻塞性呼吸道疾病模型的研究策略。这些发现可以为新的 加速解决呼吸道疾病恶化的治疗策略。

Muco-obstructive airway diseases including asthma, COPD, cystic fibrosis, and non-CF bronchiectasis have diverse genetic and environmental origins, but have certain common features that includes pathologic epithelial changes referred to as mucous metaplasia. Airway secretory cells differentiate into mucous cells with a goblet cell morphology packed with mucin granules containing MUC5AC and, to lesser extent, MUC5B. These airway diseases are characterized by frequent exacerbations due to mucous hypersecretion and blockage of the airways that leads to loss of lung function, hospitalization, and risk of death. While many of the factors that cause mucous metaplasia have been identified, little is known about how it resolves. Autophagy is a key cellular protein recycling system that degrades proteins in response to nutrient deprivation, inflammation, and infection. We have spent the last several years studying the role of autophagy in airway disease using models with genetic deletions of a key autophagy regulatory genes. In this application, we propose a new paradigm in which mucin granule degradation contributes to resolution of mucous metaplasia through the action of autophagy. Three key findings in our preliminary data support this hypothesis: First, autophagy deficient mouse and cell culture models accumulate more cytoplasmic mucin granules during mucous metaplasia and particularly during resolution. Second, mucous metaplasia is associated with mTOR activation and increased epithelial metabolism which is then down-regulate during resolution. We propose that this shift in metabolism is the key trigger initiating mucin degradation during resolution. Third, mimicking this shift in metabolism with mTOR inhibitors leads to autophagy activation and mucin degradation in human airway epithelial secretory cells. To test our hypothesis that autophagy leads to degradation of mucin granules, we propose three research aims: First, we will determine how mTOR signaling contributes to metabolism change in the secretory cell and ultimately to autophagy-mediated mucin degradation. Second, we will characterize the importance of autolysosome-lysosome fusion during mucous metaplasia resolution by examinig vesicle trafficking, lysosome biogenesis, and lysosome proteolytic function. Third, we will explore mucin degradation as a therapeutic strategy in models of muco-obstructive airway diseases. These findings can provide the framework for a new therapeutic strategy to hasten the resolution of airway disease exacerbations.