Controlling the core airway mucin secretion machinery to prevent pathophysiology

控制核心气道粘蛋白分泌机制以预防病理生理学

• 批准号: 8985701
• 负责人: Burton F Dickey
• 金额: $ 40万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8985701
• 关键词: Abbreviations; Address; Asthma; Attenuated; Binding; Breathing; Caenorhabditis elegans; Calcium; Chemicals; Chronic Obstructive Airway Disease; Coiled-Coil Domain; Complex; Coughing; Cystic Fibrosis; Cytoplasmic Granules; Disease; Environment; Eukaryota; Exocytosis; Family; Functional disorder; Gel; Genes; Germ; Glycoproteins; Golgi Apparatus; Growth; Health; Homologous Gene; Hydration status; Infection; Interstitial Lung Diseases; Knowledge; Liquid substance; Lung; Mediating; Membrane; Membrane Lipids; Membrane Protein Traffic; Mucins; Mucous body substance; Mus; Pneumonia; Production; Protein Binding; Protein Family; Protein Isoforms; Proteins; Reaction; Role; S-nitro-N-acetylpenicillamine; SNAP receptor; Scaffolding Protein; Second Messenger Systems; Signal Transduction; Solid; Structure; Synaptosomes; Testing; Vesicle; Water; Yeasts; airway obstruction; extracellular; gain of function; genetic approach; improved; knockout gene; loss of function; man; microbial; mouse model; mucus hypersecretion; particle; pathogen; prevent; protein function; public health relevance; response; scaffold; second messenger; sensor; synaptotagmin; syntaxin; syntaxin binding protein 1; target SNARE proteins; toxicant; vesicle-associated membrane protein; vesicular SNARE proteins

 DESCRIPTION (provided by applicant): 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 interstitial lung diseases. Mucin glycoproteins are the principal macromolecular component of mucus, responsible for its structure as a semi-solid gel by binding more than 100-fold their mass of water. Mucins are secreted both at a low basal rate and a high stimulated rate. A common feature of airway mucus dysfunction is the rapid secretion of overproduced 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 the differential roles of certain exocytic proteins in basal and stimulated mucin secretion allows their manipulation to augment basal secretion and inhibit stimulated secretion, attenuating the pathophysiology of mucus hypersecretion without impairing toxicant clearance. Aim 1. Determine the identity and function of the SM protein that mediates basal mucin secretion (we have already determined the identity of the SM protein in stimulated mucin secretion). Aim 2. Determine the identity and function of the Syntaxins (key components of SNARE complexes) that mediate basal and stimulated mucin secretion. Aim 3. Augment basal and inhibit stimulated mucin secretion to improve lung pathophysiology in mouse models of asthma-like airway obstruction and microbial infection. Completion of these aims will provide fundamental understanding of the mucin secretory mechanism, and build on that knowledge to test translational strategies to mitigate mucus dysfunction while preserving protective benefits of the mucus barrier.

 描述（由申请人提供）：粘液形成保护肺部免受吸入颗粒、病原体和化学品影响的基本屏障。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，粘液功能障碍促成了所有常见的气道疾病的病理生物学，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主要大分子组分，通过结合超过其质量100倍的水来负责其作为半固体凝胶的结构。粘蛋白以低基础速率和高刺激速率分泌。气道粘液功能障碍的一个共同特征是过度产生的粘蛋白快速分泌到气道腔中，形成过度粘弹性且不能通过纤毛作用清除的粘液。这阻碍了气流并为微生物生长提供了受保护的环境。虽然已经深入研究了粘蛋白产生和水合作用的控制，但对分泌的机制还不完全了解。所有真核生物中的胞吐作用都是由SNARE复合物和SM支架蛋白的协同相互作用介导的，它们是核心的胞吐机制。我们的研究表明，对于这种机制的一些组件，不同的亚型功能的基础与刺激粘蛋白分泌。我们的中心假设是某些胞外蛋白的不同作用 在基础和受刺激的粘蛋白分泌中，允许它们的操纵以增加基础分泌和抑制受刺激的分泌，减弱粘液分泌过多的病理生理学而不损害毒物清除。目标1。确定介导基础粘蛋白分泌的SM蛋白的身份和功能（我们已经确定了SM蛋白在刺激粘蛋白分泌中的身份）。目标二。确定介导基础和刺激粘蛋白分泌的突触融合蛋白（SNARE复合物的关键组分）的身份和功能。目标3。在哮喘样气道阻塞和微生物感染的小鼠模型中，增加基础和抑制刺激的粘蛋白分泌以改善肺病理生理学。这些目标的完成将提供对粘蛋白分泌机制的基本理解，并在此基础上测试翻译策略，以减轻粘液功能障碍，同时保留粘液屏障的保护作用。