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

粘膜阻塞性气道疾病，包括哮喘、慢性阻塞性肺病、囊性纤维化和非 CF 支气管扩张 不同的遗传和环境起源，但具有某些共同特征，包括病理上皮 变化称为粘液化生。气道分泌细胞通过杯状分化为粘液细胞 细胞形态充满了含有 MUC5AC 和较小程度的 MUC5B 的粘蛋白颗粒。这些气道 该疾病的特点是由于粘液分泌过多和粘膜阻塞而导致病情频繁恶化。 导致肺功能丧失、住院治疗和死亡风险的气道。虽然许多因素 粘液化生的病因已被确定，但对其如何解决却知之甚少。自噬是关键 细胞蛋白质回收系统，可响应营养缺乏、炎症和营养不良而降解蛋白质 感染。在过去的几年里，我们利用模型研究了自噬在气道疾病中的作用 关键自噬调节基因的基因缺失。在此应用中，我们提出了一种新的范式 粘蛋白颗粒降解通过以下作用有助于解决粘液化生 自噬。我们初步数据中的三个关键发现支持了这一假设：首先，自噬缺陷小鼠 细胞培养模型在粘液化生过程中积累更多的细胞质粘蛋白颗粒 特别是在决议期间。其次，粘液化生与 mTOR 激活和增加有关 上皮代谢，然后在消退过程中下调。我们认为新陈代谢的这种转变是 解决过程中启动粘蛋白降解的关键触发因素。第三，模仿这种新陈代谢的转变 mTOR 抑制剂导致人气道上皮分泌中自噬激活和粘蛋白降解 细胞。 为了检验我们的假设，即自噬导致粘蛋白颗粒降解，我们提出了三项研究 目标：首先，我们将确定 mTOR 信号传导如何促进分泌细胞的代谢变化，以及 最终导致自噬介导的粘蛋白降解。其次，我们将描述其重要性 通过检查囊泡运输、溶酶体来解决粘液化生过程中的自溶酶体-溶酶体融合 生物发生和溶酶体蛋白水解功能。第三，我们将探索粘蛋白降解作为治疗方法 粘膜阻塞性气道疾病模型的策略。这些发现可以为新的研究提供框架 加速解决气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.