Controlling the core airway mucin secretion machinery to prevent pathophysiology

粘液形成一种基本的屏障，保护肺部免受吸入颗粒、病原体和化学物质的伤害。 这些毒物被困在粘液中，然后通过纤毛作用被扫出肺部。然而，矛盾的是， 粘液功能障碍与所有常见呼吸道疾病的病理生物学有关，包括 哮喘、囊性纤维化和慢性阻塞性肺疾病，以及间质性肺部疾病。粘蛋白糖蛋白是主要的 粘液的大分子成分，通过与之相互作用而形成半固体凝胶的结构 水的质量是它们的几百倍。粘蛋白的分泌既有较低的基线速率，也有较高的 刺激率。呼吸道粘液功能障碍的一个共同特征是分泌过多的 粘蛋白进入气道腔，形成粘弹性过大且不能被纤毛清除的粘液 行动。这阻碍了气流，并为微生物的生长提供了受保护的环境 虽然粘蛋白的产生和水合的控制已经被深入研究，但分泌的机制 是不完全理解的。所有真核生物的胞吐作用都是由一种细胞因子的协同作用介导的。 SNARE复合体和SM支架蛋白，这是核心的排胞机制。我们的研究表明 对于这一机制的某些组成部分，不同的亚型在基础和刺激的粘蛋白分泌中起作用。 我们的中心假设是，两种不同的VAMP蛋白定义了两种不同类型的粘蛋白分泌 颗粒，与不同的分泌功能和不同的运输调节蛋白相关。 目的1.确定VAMP3和VAMP8在定义两个不同的结构和功能类别中的作用 粘蛋白分泌颗粒。 目的2.确定粘蛋白颗粒是如何组装的，从它们离开反式高尔基体网络到 同型融合，形成两类成熟的融合就绪颗粒。 目的3.确定操纵这两个城市交通的生理和病理生理后果 粘蛋白颗粒类。 这些目标的完成将提供对粘蛋白分泌机制的基本理解，并将 将这一知识应用于测试翻译策略，以缓解粘液功能障碍，同时保留其 保护性福利。

Mucus forms an essential barrier that protects the lungs from inhaled particles, pathogens and chemicals. These toxicants are entrapped in mucus, then swept out of the lungs by ciliary action. Paradoxically however, mucus dysfunction contributes to the pathobiology of all of the common diseases of the airways, including asthma, cystic fibrosis and COPD, as well as to interstitial lung diseases. Mucin glycoproteins are the principal macromolecular component of mucus, responsible for its structure as a semi-solid gel by interacting with several hundred-fold their mass of water. Mucins are secreted both at a low baseline rate and a high stimulated rate. A common feature of airway mucus dysfunction is the rapid secretion of hyperproduced mucins into the airway lumen, forming mucus that is excessively viscoelastic and cannot be cleared by ciliary action. This impedes airflow and provides a protected environment for microbial growth While the control of mucin production and hydration have been studied intensively, the mechanism of secretion is incompletely understood. Exocytosis in all eukaryotes is mediated by the cooperative interactions of a SNARE complex and an SM scaffolding protein, which are the core exocytic machinery. Our studies show that for some components of this machinery, different isoforms function in basal versus stimulated mucin secretion. Our central hypothesis is that two different VAMP proteins define two distinct classes of mucin secretory granules, associated with distinct secretory function and with distinct trafficking regulatory proteins. Aim 1. Determine the roles of VAMP3 and VAMP8 in defining two distinct structural and functional classes of mucin secretory granules. Aim 2. Determine how mucin granules are assembled, from their exit from the trans-Golgi network, through homotypic fusion, to form two classes of mature fusion-ready granules. Aim 3. Determine the physiological and pathophysiological consequences of manipulating the traffic of the two mucin granule classes. Completion of these aims will provide fundamental understanding of the mucin secretory mechanism, and will apply that knowledge to test translational strategies for mitigating mucus dysfunction while preserving its protective benefits.