Mechanisms of impaired mucociliary transport in CF airway disease

CF 气道疾病中粘膜纤毛运输受损的机制

基本信息

批准号：
9223992
负责人：
Mahmoud Abou Alaiwa
金额：
$ 16.02万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9223992
关键词：
Address Advisory Committees Affect Anatomy Animal Model Animals Anions Award Bicarbonates Biochemical Biology Birth Breathing Budgets Cilia Complex Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Defect Development Disease Duct (organ) structure Early treatment Elasticity Electrostatics Engineering Environment Family suidae Fostering Genes Gland Goals Grant Health Heparin High Resolution Computed Tomography Host Defense Human Image Analysis Imaging Techniques Impairment Individual Infection Inflammation Knowledge Learning Light Lung diseases Manuscripts Measures Mediating Mentors Methods Microscopy Mission Modeling Morbidity - disease rate Movement Mucins Mucociliary Clearance Mucous body substance Mutation National Heart, Lung, and Blood Institute Newborn Infant Pathogenesis Phenocopy Physicians Physiology Property Radio-Opaque Research Research Proposals Respiratory physiology Rheology Rodent Model Saline Scanning Scientist Tantalum Technical Expertise Testing Therapeutic TimeLine Training Translating Tromethamine Viscosity Work Writing X-Ray Computed Tomography airway epithelium airway surface liquid antimicrobial biophysical properties career clinical practice cystic fibrosis airway experience improved insight interest killings mechanical properties mortality new therapeutic target novel therapeutics skills student training tool viscoelasticity

项目摘要

PROJECT SUMMARY/ABSTRACT Impaired mucociliary transport (MCT) is a common feature of multiple airway diseases, including cystic fibrosis (CF). Effective MCT requires functional cilia and mucus. The mechanical properties of mucus influence MCT. In CF, loss of bicarbonate transport in the airway epithelium decreases the pH of the airway surface liquid (ASL). The acidic ASL changes the electrostatic interactions of mucus, making the mucus more viscous. This defect is present at birth prior to the onset of infection and inflammation. Newborn CF pigs also have impaired MCT. We predict that the viscous mucus in newborn CF pigs gives rise to defective MCT. In the current application, the candidate will probe the biophysical properties of freshly isolated porcine airway mucus using agents that alter mucus electrostatic interactions. He will assess the biophysical properties using passive microrheology. Concomitantly, he will measure MCT in newborn CF pigs using computed tomography (CT) and correlate how altered biophysical properties of mucus influence MCT. The candidate's long-term career goal is to become a leader in the fields of airway biology and airway disease. He plans to advance both fields by utilizing advanced imaging techniques and porcine models. The selection of the porcine model is particularly relevant because the airway anatomy and physiology more closely resemble humans than traditional rodent models. In the current K08 application, the candidate will gain multiple intellectual, professional and technical skills to foster his development into an independent and successful physician scientist. He has an outstanding mentor and advisory committee that will guide him in learning passive microrheology of mucus and whole animal CT. This topic is highly significant as mucus biophysical properties influence MCT, and thus the candidate's work can shed light on basic biology and also potential therapeutics. In addition, the candidate will continue to develop his manuscript and grant writing abilities through reviewing of manuscripts and grants under Dr. Welsh's guidance. He will also take coursework in biomedical and biochemical engineering to advance his understanding of the complex principles of rheology and imaging analyses. Lastly, the candidate will continue to cultivate his own mentoring skills through learning how to manage timelines and budgets, as well as train junior scientists. In summary, this award will greatly enrich the candidate's career by providing him with additional tools necessary to become an independent and successful physician scientist that contributes to the betterment of human health.

项目概要/摘要粘膜纤毛运输 (MCT) 受损是多种气道疾病的共同特征，包括囊性纤维化（CF）。有效的 MCT 需要有功能的纤毛和粘液。粘液的机械特性影响 MCT。在CF中，气道上皮中碳酸氢盐运输的损失降低了气道表面液体的pH值（美国手语）。酸性 ASL 改变了粘液的静电相互作用，使粘液更加粘稠。这在感染和炎症发生之前出生时就存在缺陷。新生CF猪也有受损 MCT。我们预测新生 CF 猪的粘稠粘液会导致 MCT 缺陷。在当前的申请中，候选人将探测新鲜分离的猪气道的生物物理特性粘液使用改变粘液静电相互作用的试剂。他将使用以下方法评估生物物理特性被动微流变学。与此同时，他将使用计算机断层扫描测量新生 CF 猪的 MCT (CT) 并关联粘液生物物理特性的改变如何影响 MCT。候选人的长期职业目标是成为气道生物学和气道疾病领域的领导者。他计划利用先进的成像技术和猪模型来推进这两个领域的发展。评选猪模型的研究尤其重要，因为其气道解剖学和生理学更加密切与传统的啮齿动物模型相比，它更类似于人类。在目前的K08申请中，候选人将获得多种智力、专业和技术技能，以促进他发展成为一名独立且成功的医师科学家。他有一位出色的导师以及指导他学习粘液被动微流变学和全动物CT的咨询委员会。该主题非常重要，因为粘液生物物理特性会影响 MCT，从而影响候选人的工作可以阐明基础生物学和潜在的治疗方法。此外，候选人将继续通过审查博士的手稿和资助，发展他的手稿和资助写作能力。威尔士的指导。他还将学习生物医学和生物化学工程课程，以提高他的水平了解流变学和成像分析的复杂原理。最后，候选人将继续通过学习如何管理时间表和预算以及培训来培养自己的指导技能青年科学家。总之，该奖项将为候选人提供额外的工具，极大地丰富他的职业生涯成为一名独立且成功的医师科学家，为改善人类健康做出贡献所必需的人类健康。