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

• 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
• 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

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 粘液清除系统是机体抵抗吸入性感染的主要防御系统 代理和毒素。然而，尽管两个多世纪的研究，粘液清除的性质， 然而，我们对这一体系的基本方面的认识仍然存在令人惊讶的差距。填补这些空白的是 这对改善防治呼吸道传染病的公共卫生战略十分重要。填补这些空白 对于阐明慢性肺疾病的发病机理和开发慢性肺疾病的治疗也是重要的， 包括COPD、哮喘、NCFB和罕见遗传病（CF、PCD），根据定义，其特征在于 肺内粘液积聚。这个PPG建议调查基本的，但知之甚少的方面， 粘液清除系统，必须量化，以了解粘液功能在健康和功能障碍 疾病。每个PPG项目都有两个具体目标，一个侧重于基本粘蛋白功能，另一个侧重于 粘蛋白病理生物学的翻译方面。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， 在粘液层中。这些研究将通过添加“异常聚合物”的研究加以补充， 例如，在一个实施例中，从DNA到粘液溶液。项目2（“为什么粘蛋白如此巨大，切断它们是否安全/有效 治疗？"，Richard C. Boucher，MD，PI）将重点讨论为什么人体气道 粘蛋白聚合物具有如此巨大的尺寸（300 MDa，Rg 250 nm），并且表征了功效比（链 长度减少）与开发治疗肺部疾病的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”， 布赖恩按钮，博士，PI）将研究纤毛，PCL和运输所需的粘液层之间的关系， 集中在一个新的液压“推”与经典的“抓”机制。此外，PCL的屏障功能 并对其进行研究。项目4（“呼吸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体粘液”，Ronit Freeman，PhD，PI）将关注一种新的属性 粘膜下腺（SMG）粘液，一种链/束不溶性组分，以及链/束如何贡献 SMG粘液功能在健康和疾病。三个核心支持PPG：1）核心A， 管理/生物统计核心，多PI Richard C.鲍彻，医学博士和迈克尔鲁宾斯坦，博士，用品 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/生物物理学提供所有粘蛋白试剂的质量控制 3）核心C，成像核心，PI Camille Ehre，PhD，提供电子显微镜， 分子和形态分析的项目。PPG的总体目标是阐明结构 粘液在健康中的作用，这些特征如何在疾病中降解，并确定 开发治疗粘膜阻塞性疾病的新型治疗剂。