The role of mucin-protein interactions in the innate defense of the lung

粘蛋白-蛋白质相互作用在肺先天防御中的作用

基本信息

批准号：
8116579
负责人：
Mehmet Kesimer
金额：
$ 37万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-21 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8116579
关键词：
Affinity Antioxidants Asthma Behavior Binding Binding Proteins Biochemical Biological Assay C-terminal Cell Culture Techniques Chemicals Chimeric Proteins Chronic Bronchitis Chronic lung disease Complex Coughing Coupled Cystic Fibrosis DMBT1 gene Data Defensins Ensure Epithelial Epithelial Cells Excision Fluorescein-5-isothiocyanate Fluorescence Recovery After Photobleaching Future Gel Glycopeptides Glycoproteins Goals Gold Colloid Heart Human Immune system Immunoelectron Microscopy Infection Inflammation Knowledge Label Lead Lung MUC5AC gene MUC5B gene Mass Spectrum Analysis Measurement Measures Mechanics Methods Microspheres Molecular Molecular Weight Molecular and Cellular Biology Morbidity - disease rate Mucins Mucous body substance Predisposition Property Protein Binding Protein Region Protein-Carbohydrate Interaction Proteins Proteomics Quartz Refractive Indices Retinal Cone Rheology Role Structure Surface Tertiary Protein Structure Testing Therapeutic Intervention Tracheobronchial Western Blotting antimicrobial base design disease characteristic globular protein liquid chromatography mass spectrometry mortality novel protein complex protein structure public health relevance research study respiratory

项目摘要

DESCRIPTION (provided by applicant): The airway epithelial mucosal barrier is the heart of a powerful innate immune system that maintains the underlying epithelial surface. At the broadest level, the major scientific goal of this proposal is to elucidate the organization of the airway gel layer, which is formed by very large glycoproteins termed mucins (MUC5B and MUC5AC) coupled with other protective biomolecules through labile interactions, and assess the role of these interactions in airway mucus integrity as an essential pre-requisite for therapeutic intervention. Our hypothesis is that normal airway mucus is highly structured, containing an excess of 100 proteins that form distinct protein complexes many of which are centered around these mucins. These complexes constitute a discrete secretory entity we call the 'mucin interactome'. We propose that gel properties emerge from a dynamic interplay between the mucins and proteins and that these structures engender specific rheological properties of mucus that tune it to removal by cough and flow clearance. This proposal will change the paradigm that mucins are the only molecules that give most of the rheological properties to mucus and will ultimately lead to a greater understanding of the role of these interactions as an innate defense of the lung. In testing these hypotheses, using a broad range of biochemical, molecular and cellular biology methods, we propose: 1) To determine our target panel of proteins that show evidence of specific mucin binding; 2) To determine the domains required for the mucin-protein interactions and 3) To assess the effects of mucin-protein interactions on the surface and bulk rheological properties of the mucus. If the goals of this proposal are achieved, they will increase our knowledge and understanding of the relationship between protein composition and the function of airway secretions. Such knowledge is an essential pre-requisite for informed therapeutic intervention. PUBLIC HEALTH RELEVANCE: This proposal will examine the organization of the airway gel layer formed by very large glycoproteins, termed mucins, coupled to other protective biomolecules through labile interactions, and assess their role on airway mucus integrity and function. This is a novel proposal and will change the paradigm that mucins are the only molecules that give most of the rheological properties to mucus and, if true, will ultimately lead to a greater understanding of the role of these interactions as an innate defense of the lung.

描述（由申请人提供）：气道上皮粘膜屏障是维持下层上皮表面的强大先天免疫系统的核心。在最广泛的层面上，该提案的主要科学目标是阐明气道凝胶层的组织，该凝胶层是由称为粘蛋白（MUC5B 和 MUC5AC）的非常大的糖蛋白通过不稳定的相互作用与其他保护性生物分子结合形成的，并评估其作用气道粘液完整性中的这些相互作用是治疗干预的重要先决条件。我们的假设是，正常气道粘液是高度结构化的，含有超过 100 种蛋白质，这些蛋白质形成不同的蛋白质复合物，其中许多以这些粘蛋白为中心。这些复合物构成了一个离散的分泌实体，我们称之为“粘蛋白相互作用组”。我们认为，凝胶特性是由粘蛋白和蛋白质之间的动态相互作用产生的，并且这些结构产生了粘液的特定流变特性，从而调节粘液通过咳嗽和流量清除而去除。这一提议将改变粘蛋白是唯一赋予粘液大部分流变特性的分子的范式，并最终使人们更好地理解这些相互作用作为肺部先天防御的作用。在测试这些假设时，我们使用广泛的生化、分子和细胞生物学方法，建议：1) 确定显示特定粘蛋白结合证据的目标蛋白质组； 2) 确定粘蛋白-蛋白质相互作用所需的结构域，以及 3) 评估粘蛋白-蛋白质相互作用对粘液表面和整体流变特性的影响。如果该提案的目标得以实现，将增加我们对蛋白质组成与气道分泌物功能之间关系的认识和理解。这些知识是知情治疗干预的重要先决条件。公共健康相关性：该提案将检查由非常大的糖蛋白（称为粘蛋白）形成的气道凝胶层的组织，通过不稳定的相互作用与其他保护性生物分子偶联，并评估它们对气道粘液完整性和功能的作用。这是一个新颖的提议，将改变粘蛋白是唯一赋予粘液大部分流变特性的分子的范式，如果属实，最终将导致人们更好地理解这些相互作用作为肺部先天防御的作用。。