Mechanisms of impaired mucociliary transport in CF airway disease

项目摘要/摘要 粘液纤毛转运受损(MCT)是包括囊性纤维化在内的多种呼吸道疾病的共同特征 (Cf)。有效的MCT需要有功能的纤毛和粘液。粘液的力学性质影响MCT。 在慢性阻塞性肺疾病中，重碳酸盐在呼吸道上皮细胞中运输的丧失降低了呼吸道表面液体的pH值 (ASL)。酸性的ASL改变了粘液的静电相互作用，使粘液更粘性。这 出生缺陷在感染和炎症发生之前就存在了。新生的CF猪也受到了损害 MCT。我们预测，新生CF猪体内粘稠的粘液会导致MCT缺陷。 在目前的应用中，候选人将探测新鲜分离的猪呼吸道的生物物理特性 使用改变粘液静电相互作用的试剂的粘液。他将使用以下方法评估生物物理特性 被动微观流变学。与此同时，他将使用计算机断层扫描技术测量新生的CF猪的MCT (CT)，并关联粘液的生物物理性质改变如何影响MCT。 候选人的长期职业目标是成为呼吸道生物学和呼吸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动这两个领域的发展。精选 尤其与猪模型相关，因为呼吸道解剖学和生理学更密切 比传统的啮齿动物模型更像人类。 在目前的K08申请中，应聘者将获得多种智力、专业和技术技能，以 把他培养成一名独立、成功的内科科学家。他有一位杰出的导师 和顾问委员会，将指导他学习被动粘液微观流变学和整个动物CT。 这个主题非常有意义，因为粘液的生物物理性质会影响MCT，从而影响候选人的工作 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 通过对手稿和助学金的审阅，培养他的手稿和写作能力。 威尔士人的指导。他还将学习生物医学和生化工程方面的课程，以提升他的 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以及培训来培养自己的指导技能 初级科学家。 总之，这一奖项将为候选人提供更多的工具，从而极大地丰富他的职业生涯 成为一名独立和成功的内科科学家所必需的，为改善 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.