Multi-Scale Investigations of Respiratory Mucus/Mucin Structure and Function in Health and Disease

健康和疾病中呼吸道粘液/粘蛋白结构和功能的多尺度研究

基本信息

批准号：
10684185
负责人：
Richard Charles Boucher
金额：
$ 275.76万
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：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684185
关键词：
Address Air Asthma Binding Biochemical Biochemistry Biological Biology Biophysics Biostatistics Core Bronchiectasis Cactaceae Characteristics Chronic Chronic Obstructive Pulmonary Disease Chronic lung disease Cilia Ciliary Motility Disorders Claw Communicable Diseases Complement Cystic Fibrosis DNA Development Disease Distal Doctor of Philosophy Electrons Electrostatics Elements Ensure Failure Functional disorder Gel Genes Genetic study Geometry Gland Goals Health Host Defense Human Hydration status Hydrophobicity Image In Vitro Infectious Agent Inhalation Investigation Knowledge Left Length Lung Lung diseases Measurement Membrane Microscopic Molecular Molecular Biology Morphology Mucins Mucolytics Mucous body substance Mus Nature Obstruction Outcome Pathogenesis Patients Polymers Population Power stroke Predisposition Property Public Health Pump Quality Control Reagent Recording of previous events Regulation Research Research Personnel Respiratory Disease Respiratory Mucin Risk Role Series Skin Slide Stretching Structure Submucosa Surface System Tandem Repeat Sequences Testing Therapeutic Therapeutic Agents Toxic Environmental Substances Toxin Water Work airway surface liquid aqueous biophysical properties combat crosslink dimer effective therapy fluid flow genetic approach improved in vivo lung health mucus clearance mucus-associated lung diseases neutrophil novel novel therapeutics rare genetic disorder respiratory therapy development transmission process treatment strategy viscoelasticity

项目摘要

OVERALL ABSTRACT The mucus clearance system constitutes the primary airway host defense system against inhaled infectious agents and toxins. However, despite more than two centuries of research into the nature of the mucus clearance system, surprising gaps in our knowledge of fundamental aspects of this system persist. Filling in these gaps is important for improving public health strategies to combat respiratory infectious diseases. Filling in these gaps is also important for elucidating the pathogenesis of and developing therapies for chronic pulmonary diseases, including COPD, asthma, NCFB, and rare genetic diseases (CF, PCD), which are by definition characterized by mucus accumulation in the lung. This PPG proposes to investigate fundamental, but poorly understood, aspects of the mucus clearance system that must be quantitated to understand mucus function in health and dysfunction in disease. Each PPG project has two specific aims focused on basic mucin function and one focused on translational aspects of mucin pathobiology. Project 1 (“Mucin Structure and Associations in Respiratory Mucus”, Michael Rubinstein, PhD, PI) will investigate fundamental aspects of the organization of mucins in solution and within the mucus layer. These studies will be complemented by studies of the addition of “abnormal polymers”, e.g., DNA, to mucus solutions. Project 2 (“Why are mucins so gigantic and is it safe/effective to sever them therapeutically?”, Richard C. Boucher, MD, PI) will focus on the fundamental question as to why human airway mucin polymers are of such enormous size (300 MDa, Rg 250 nm) and characterize the ratio of efficacy (chain length reduction) vs risk (off-target chain unwinding) required for the development of mucolytics for lung disease. Project 3 (“Membrane-bound mucins on the airway surface ensure efficient mucus clearance and lung health”, Brian Button, PhD, PI) will study the relationships between cilia, PCL, and the mucus layer required for transport, focusing on a novel hydraulic “pushing” vs classic “clawing” mechanisms. In addition, barrier functions of PCL and regulation thereof will be studied. Project 4 (“Biophysical and structural characterization of airway submucosal gland mucus in health and cystic fibrosis”, Ronit Freeman, PhD, PI) will focus on a novel attribute of submucosal gland (SMG) mucus, a strand/bundle insoluble component, and how strands/bundles contribute to SMG mucus function in health and disease. Three cores support the PPG: 1) Core A, the Administrative/Biostatistical Core, Multi-PIs Richard C. Boucher, MD, and Michael Rubinstein, PhD, supplies project management and statistical support for the PPG; 2) Core B, the Mucus/Mucin Analytics Core, PI Mehmet Kesimer, PhD, provides quality control of all mucin reagents for the PPG and novel biochemical/biophysical measurements; and 3) Core C, the Imaging Core, PI Camille Ehre, PhD, provides electron microscopic, molecular, and morphologic analyses to the projects. The overall goals of the PPG are to elucidate the structure and function of mucus in health, how these characteristics are degraded in disease, and identify strategies for development of novel therapeutic agents to treat muco-obstructive diseases.

总体摘要粘液清除系统构成抵抗吸入传染性病毒的主要气道宿主防御系统然而，尽管对粘液清除的性质进行了两个多世纪的研究。系统，我们对该系统的基本方面的了解仍然存在令人惊讶的差距，填补这些空白是。对于改善应对呼吸道传染病的公共卫生策略非常重要。对于阐明慢性肺部疾病的发病机制和开发治疗方法也很重要，包括 COPD、哮喘、NCFB 和罕见遗传病（CF、PCD），根据定义，这些疾病的特征是该 PPG 提议研究基本但知之甚少的方面。必须对粘液清除系统进行定量，以了解健康和功能障碍中的粘液功能每个 PPG 项目都有两个专注于基本粘蛋白功能的具体目标，一个专注于疾病。粘蛋白病理学的转化方面项目 1（“呼吸道粘液中的粘蛋白结构和关联”， Michael Rubinstein，博士，PI）将研究溶液中粘蛋白组织的基本方面，这些研究将通过添加“异常聚合物”的研究来补充，例如，DNA，到粘液解决方案 2（“为什么粘蛋白如此巨大，切断它们是否安全/有效”）治疗上？”，Richard C. Boucher，医学博士，PI）将重点关注人类气道为何会出现这种基本问题粘蛋白聚合物的尺寸如此之大（300 MDa，Rg 250 nm），并且表征了功效比（链长度减少）与开发肺部疾病粘液溶解剂所需的风险（脱靶链解旋）。项目 3（“气道表面的膜结合粘蛋白确保有效的粘液清除和肺部健康”） Brian Button（博士、PI）将研究纤毛、PCL 和运输所需的粘液层之间的关系，重点关注新型液压“推”与经典“抓”机制此外，PCL 的屏障功能。将研究项目 4（“气道的生物物理和结构特征”）。健康和囊性纤维化中的粘膜下腺粘液”，Ronit Freeman 博士，PI）将重点关注一个新属性粘膜下腺 (SMG) 粘液、链/束不溶性成分以及链/束如何发挥作用 SMG 粘液功能在健康和疾病中的三个核心支持 PPG：1) 核心 A，即行政/生物统计核心、多 PI Richard C. Boucher（医学博士）和 Michael Rubinstein（博士）提供材料 PPG 的项目管理和统计支持；2) 核心 B，粘液/粘蛋白分析核心，PI Mehmet Kesimer 博士为 PPG 和新型生物化学/生物物理的所有粘蛋白试剂提供质量控制 3) Core C，成像核心，PI Camille Ehre 博士，提供电子显微镜、 PPG 的总体目标是阐明结构。粘液在健康中的作用和功能，这些特征在疾病中如何退化，并确定治疗策略开发治疗粘膜阻塞性疾病的新型治疗剂。