Diversity Supplement for PhD student Shamarie King under Multi-Scale Investigations of Respiratory Mucus/Mucin Structure and Function in Health and Disease

博士生 Shamarie King 在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中的多样性补充

• 批准号: 10852415
• 负责人: Richard Charles Boucher
• 金额: $ 10.26万
• 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/10852415
• 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; doctoral student; 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.

总体抽象 粘液间隙系统构成了针对吸入感染性的主要气道宿主防御系统 特工和毒素。但是，尽管对粘液清除性质的性质进行了超过两个世纪的研究 系统，我们对该系统基本方面的了解的惊喜差距持续存在。填补这些空白是 对于改善抗击呼吸道传染病的公共卫生策略至关重要。填补这些空白 对于阐明慢性肺部疾病的疗法的发病机理也很重要， 包括COPD，哮喘，NCFB和稀有遗传疾病（CF，PCD），其定义为以定义为特征 粘液在肺部积累。这项PPG提出了调查基本但不理解的方面的建议 必须量化的粘液清除系统，以了解健康和功能障碍的粘液功能 在疾病中。每个PPG项目都有两个具体目标，重点是基本粘蛋白功能，一个专注于 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”， 迈克尔·鲁宾斯坦（Michael Rubinstein）博士，PI）将调查粘液组织在解决方案和 在粘液层中。这些研究将通过添加“异常聚合物”的研究完成， 例如，DNA，用于粘液溶液。项目2（“为什么粘液如此巨大，对他们有些安全/有效 在治疗上？”，理查德·C·鲍彻（Richard C. 粘蛋白聚合物具有巨大的尺寸（300 MDA，RG 250 nm），并且表征了效率的比率（链 降低长度）与开发肺部疾病粘液溶剂所需的风险（脱靶链）。 项目3（“气道表面上的膜结合的粘蛋白可确保有效的粘液清除和肺部健康”， Brian Button，PhD，PI）将研究CILIA，PCL和运输所需的粘液层之间的关系 专注于一种新型的水解“推动”与经典的“爪”机制。此外，PCL的障碍功能 并将其法规进行研究。项目4（“气道的生物物理和结构表征 健康和囊性纤维化中的粘膜粘膜粘液”，Ronit Freeman，PHD，PI）将重点放在新型属性上 粘膜粘膜（SMG）粘液，链/束不溶性组件以及链/束的贡献 smg粘液在健康和疾病中的功能。三个内核支持PPG：1）核心A， 行政/生物统计学核心，Multi-Pis Richard C. Boucher，医学博士和Michael Rubinstein博士 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博士提供了PPG和新型生化/生物物理的所有粘蛋白试剂的质量控制 测量； 3）核心C，成像核心Pi Camille EHRE博士提供电子显微镜， 分子和对项目的形态分析。 PPG的总体目标是阐明结构 粘液在健康中的功能，这些特征如何在疾病中降解，并确定策略 开发新型的热剂来治疗粘液刺激性疾病。

项目成果

Nanocolloidal hydrogel mimics the structure and nonlinear mechanical properties of biological fibrous networks.

• DOI: 10.1073/pnas.2220755120
• 发表时间: 2023-12
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Elisabeth Prince;S. Morozova;Zhengkun Chen;Vahid Adibnia;I. Yakavets;Sergey Vladimir Panyukov;M. Rubinst

Entropic Mixing of Ring/Linear Polymer Blends.

• DOI: 10.1021/acspolymersau.2c00050
• 发表时间: 2023-04-12
• 期刊: ACS polymers Au
• 作者: Grest GS;Ge T;Plimpton SJ;Rubinstein M;O'Connor TC
• 通讯作者: O'Connor TC