Mechanism of mucus pathology in asthma exacerbations

哮喘加重中的粘液病理机制

• 批准号: 9027708
• 负责人: John V Fahy
• 金额: $ 49.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027708
• 关键词: Acetylcysteine; Acute; Address; Amino Acids; Asthma; Attention; Behavior; Breathing; Carbohydrates; Cessation of life; Characteristics; Clinical; Cysteine; Cysteine-Rich Domain; Data; Disease; Disulfide Linkage; Disulfides; Drug usage; Elasticity; Figs - dietary; Formulation; Galactose; Gel; Goals; Grant; Hand; Hand functions; Health; Hydrogels; Inflammation; Inhalators; Irritants; LIM Domain; Libraries; Measures; Mediating; Methods; Mucins; Mucolytics; Mucous body substance; Nature; Obstruction; Odors; Oxidative Stress; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Play; Polymers; Powder dose form; Property; Public Health; Reducing Agents; Rheology; Role; Sputum; Stimulus; Structure; Structure-Activity Relationship; Sulfhydryl Compounds; Symptoms; Testing; Therapeutic; Universities; airway inflammation; airway obstruction; analog; asthmatic; carbohydrate structure; college; cost; crosslink; disulfide bond; drug development; hydroxyl group; monomer; novel; novel therapeutics; oxidation; particle; pathogen; physical property; practical application; programs; scaffold; solid state; therapeutic target; treatment strategy

 DESCRIPTION (provided by applicant): Pathologic mucus is a major problem in asthma exacerbations, contributing significantly to mechanisms of airflow obstruction, and playing a major role in death from asthma. Despite this important role for mucus in asthma exacerbations, the mechanism underlying the formation of "rubbery" occlusive mucus in asthma have been poorly understood, and mucolytic therapies are limited in number, efficacy, and tolerability. Recently, the Fahy lab has shown that excessive numbers of mucin disulfide bonds represent a therapeutic target in pathologic mucus gels. In addition, the lab has shown that disulfide bonds can be broken with reducing agents such as N-acetyl cysteine (NAC). Because of the significant limitations of NAC as a therapeutic, we have collaborated with the Oscarson lab at University College Dublin to explore the utility of reducing agents using thiol-modified saccharides ("thiol-saccharides"). The rationale behind choosing a carbohydrate scaffold is that they are polar, cheap, "natural", often crystalline, and, with their abundance of hydroxyl groups as well as chiral centers, offer easy access to analogues for structure activity relationship (SAR) studies. Preliminary data show high mucolytic efficacy for a candidate thiol-saccharides with multiple advantages over NAC, including faster onset of action and better potency. We propose three Aims to advance understanding of mucus pathology in acute severe asthma and to hasten a new drug development program for thiol-saccharides as a novel mucolytic treatment for mucus pathology in acute asthma. Aim 1 will explore the role of oxidative stress as a mechanism of mucus pathology in acute severe asthma. Aim 2 will synthesize a library of thiol-saccharides and evaluate their physicochemical properties, aerosolization characteristics, and stability as spray dried compounds with the goal to optimize formulation of their delivery as a dry powder. Aim 3 will test whether thiol- saccharides can effectively liquefy mucus in acute severe asthma.

 描述（由适用提供）：病理性粘液是哮喘加重的主要问题，对气流异议的机制产生了重大贡献，并且在哮喘死亡中起了重要作用。尽管粘液在哮喘加剧中的这种重要作用，但哮喘中“橡胶”闭塞性粘液形成的机制知之甚少，并且粘液溶解疗法的数量，有效性和耐受性受到限制。最近，Fahy Lab表明，超过数量的粘蛋白二硫键代表了病理粘液凝胶中的治疗靶标。此外，该实验室表明，二硫键可以通过还原剂（例如N-乙酰半胱氨酸（NAC））破裂。由于NAC作为一种疗法的显着局限性，我们与都柏林大学大学的Oscarson实验室合作，使用硫醇改性糖（“硫代糖”）探索了减少剂的实用性。选择碳水合物支架背后的理由是它们是极性的，便宜的，“天然的”，通常是结晶的，并且具有丰富的羟基以及手性 中心，可轻松访问结构活动关系（SAR）研究的类比。初步数据显示，候选硫代糖含量高于NAC，包括更快的动作发作和更好的效力。我们提出三个旨在提高急性严重哮喘中粘液病理学的了解，并促进针对硫代糖的新药物开发计划，作为一种新型的脂肪性治疗，用于急性哮喘中的粘液病理学。 AIM 1将探索氧化应激作为急性严重哮喘中粘液病理的机制。 AIM 2将综合硫醇 - 含糖的库，并评估其物理特性，航空学特征和稳定性，因为喷雾干燥的化合物的目标是优化其作为干粉的递送式。 AIM 3将测试硫代糖是否可以有效地在急性严重哮喘中液化粘液。