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.

项目摘要/摘要受损的粘膜纤毛运输（MCT）是多种气道疾病的共同特征，包括囊性纤维化（CF）。有效的MCT需要功能性纤毛和粘液。粘液的机械性能影响MCT。在CF中，气道上皮中碳酸氢盐转运的损失降低了气道表面液体的pH值（ASL）。酸性ASL会改变粘液的静电相互作用，从而使粘液更粘。这缺陷在感染和炎症发作之前出生时存在。新生儿CF猪也受到了损害 MCT。我们预测，新生儿猪中的粘性粘液会导致MCT缺陷。在当前的应用中，候选人将探测新鲜分离的猪气道的生物物理特性使用改变粘液静电相互作用的药物的粘液。他将使用被动微流变学。随之而来的是，他将使用计算机断层扫描来测量新生CF猪的MCT （CT）并将粘液影响MCT的生物物理特性改变。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。他计划通过使用先进的成像技术和猪模型来推进这两个领域。选择猪模型特别相关，因为气道解剖学和生理学更接近比传统的啮齿动物模型类似于人类。在当前的K08应用程序中，候选人将获得多种知识，专业和技术技能将他的发展促进了独立，成功的医师科学家。他有一位出色的导师和咨询委员会将指导他学习粘液和整个动物CT的被动微笑学。该主题非常重要，因为粘液生物物理特性会影响MCT，因此候选人的工作可以阐明基本生物学以及潜在的治疗剂。此外，候选人将继续通过审查Dr. 威尔士的指导。他还将参加生物医学和生化工程的课程，以促进他的理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初级科学家。总而言之，通过为候选人提供其他工具，该奖项将极大地丰富候选人的职业生涯成为一名独立和成功的医师科学家所必需的，这有助于改善人类健康。