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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.

整体的抽象