Mechanisms of impaired mucociliary transport in CF airway disease

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。这个 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 通过在博士的指导下审查手稿和资助，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。

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.