Controlling the core airway mucin secretion machinery to prevent pathophysiology

粘液形成了一个重要的屏障，保护肺部免受吸入颗粒，病原体和化学品的侵害。 这些有毒物质包埋在粘液中，然后通过纤毛的作用被清除出肺。然而奇怪的是， 粘液功能障碍导致所有常见的气道疾病的病理学，包括 哮喘、囊性纤维化和COPD以及间质性肺病。粘蛋白糖蛋白是 粘液的大分子成分，通过与 是它们质量的几百倍粘蛋白以低基线速率和高基线速率分泌。 刺激率气道粘液功能障碍的一个共同特征是快速分泌高分泌的 粘蛋白进入气道腔，形成过度粘弹性且不能被纤毛清除的粘液。 行动上这阻碍了气流，为微生物的生长提供了一个受保护的环境 虽然已经深入研究了粘蛋白产生和水合作用的控制，但分泌的机制仍然是不确定的。 是不完全理解的。所有真核生物中的胞吐作用都是由一个 SNARE复合物和SM支架蛋白，它们是核心的胞外机械。我们的研究表明， 对于这种机制的某些组分，不同的同种型在基础与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的粘蛋白分泌类型， 颗粒，与不同的分泌功能和不同的运输调节蛋白。 目标1。确定VAMP 3和VAMP 8在定义两种不同的结构和功能类别中的作用， 粘蛋白分泌颗粒。 目标二。确定粘蛋白颗粒是如何组装的，从它们从trans-Golgi网络的出口， 同型融合，以形成两类成熟的融合就绪颗粒。 目标3。确定操纵两者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， 应用这些知识来测试减轻粘液功能障碍的翻译策略，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.