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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.

项目总结/文摘