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Role of Mucin in Lung Homeostasis and Pathophysiology

粘蛋白在肺稳态和病理生理学中的作用

基本信息

批准号：
10115780
负责人：
Christopher M Evans
金额：
$ 59.65万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115780
关键词：
Acute Affect Air Movements Allergic Anabolism Animals Applied Genetics Area Asthma Automobile Driving Award Biology Biomedical Engineering Breathing C-terminal CRISPR/Cas technology Cell Culture Techniques Cells Complement Cysteine Data Development Devices Disease Disulfides Economics Exposure to Extrinsic asthma Face Functional disorder Gel Glycoproteins Health Health Care Costs Homeostasis Human Impairment Inhalation Interleukin-13 Intervention Knockout Mice Laboratories Link Lung Lung diseases MUC5AC gene MUC5B gene Mediating Modeling Molecular Mucins Mucociliary Clearance Mucolytics Mucous body substance Mus Mutant Strains Mice Mutation N-terminal Obstruction Pathologic Personal Satisfaction Phenotype Physiological Point Mutation Polymers Positioning Attribute Prevention Prevention strategy Property Protein Isoforms Proteins Reducing Agents Research Rheology Role Sampling Severity of illness Sputum Technology Testing Therapeutic Agents Therapeutic Uses Thick Thinness Transgenic Mice airway epithelium airway hyperresponsiveness cytokine disulfide bond effective therapy extracellular improved in vivo innovation macromolecular assembly macromolecule novel novel strategies particle polymerization preservation prevent public health relevance tool viscoelasticity von Willebrand Factor

项目摘要

PROJECT SUMMARY/ABSTRACT Although mucus is a defensive barrier that is critical for maintaining healthy lungs, excessive mucus is a significant pathological contributor to lung diseases. The disparate faces of mucus function and dysfunction epitomize the need for tightly controlling the predominant macromolecules in airway mucus - the polymeric mucins MUC5AC and MUC5B. In asthma, mucus viscoelasticity increases and causes airflow and mucociliary clearance (MCC) impairments that are not adequately treated. We postulate that by determining specific molecular mechanisms of MUC5AC and MUC5B biosynthesis, we will identify novel mechanisms and potential treatments for improving airway mucus function and dysfunction. We previously demonstrated significant functions for Muc5ac and Muc5b in knockout mice. We now seek to interrogate how Muc5ac and Muc5b function as polymers. Muc5ac and Muc5b assemble by inter-molecular disulfide bonding at their cysteine-rich carboxyl (C-) and amino (N-) termini, resulting in the formation of massive glycopolymers. Recently, we treated allergically inflamed mice with inhaled agents that disrupted mucin polymer disulfide bonds, and we found that mucus viscoelasticity, MCC, and airflow function all improved. While inhaled mucolytics could be useful, there are currently no safe or effective options available for therapeutic use. Thus, there is further need to determine MUC5AC and MUC5B isoform specific polymer functions. We hypothesize that mucus function and dysfunction are dictated by specific mucin isoform expression and disulfide polymerization mechanisms that regulate mucus viscoelastic gel and transport properties. We will test the following hypotheses in thee Specific Aims: 1) that isoform specific mucin polymers mediate AHR and MCC; 2) that polymerization is mediated by disulfide bonds between conserved cysteine residues in the N- and C-termini of MUC5AC/Muc5ac and MUC5B/Muc5b; and 3) that conserved N- and C-terminal cysteines are required for mucin isoform-specific polymerization and function in vivo. We will conduct studies in mucin mutant mice, in human mucus samples, in airway epithelial cell cultures, and with bioengineered Human Small Airway-on-a-Chip devices. Successful completion of the Aims proposed here will further advance our understanding of mucin polymer formation and function in the airways. Our studies could also identify improved strategies for preventing obstruction while preserving defensive mucus functions that are required for lung health.

项目总结/文摘