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

• 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
• 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

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/摘要 黏膜纤毛转运受损（MCT）是包括囊性纤维化在内的多种气道疾病的共同特征 （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 （美国手语）。酸性ASL改变粘液的静电相互作用，使粘液更粘稠。这 缺陷是在出生时感染和炎症发作之前就存在的。新生CF猪也有受损 MCT。我们预测新生CF猪的粘性粘液会导致MCT缺陷。 在目前的应用中，候选人将探测新鲜分离的猪气道的生物物理特性 粘液使用改变粘液静电相互作用的试剂。他将评估生物物理特性， 被动微观流变学同时，他将使用计算机断层扫描测量新生CF猪的MCT (CT)并将粘液的生物物理性质的改变如何影响MCT相关联。 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。 他计划通过利用先进的成像技术和猪模型来推进这两个领域。选择 猪模型的气道解剖学和生理学更接近于 比传统的啮齿动物模型更像人类 在目前的K 08申请中，候选人将获得多种智力，专业和技术技能， 培养他成为一名独立和成功的医生科学家。他有一位杰出的导师 和咨询委员会，将指导他学习被动粘液和整个动物CT的微观流变学。 这个主题是非常重要的粘液生物物理特性影响MCT，因此候选人的工作 可以揭示基础生物学和潜在的治疗方法。此外，候选人将继续 通过审阅博士的手稿和赠款，发展他的手稿和资助写作能力。 威尔士的指导。他还将参加生物医学和生物化学工程的课程，以提高他的 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，培养自己的指导技能，以及培训 初级科学家 总之，这个奖项将大大丰富候选人的职业生涯，为他提供额外的工具 必须成为一个独立的和成功的医生科学家，有助于改善 人体健康