Neural Pathogenesis of Airway Smooth Muscle Defects in Airway Disease

描述（由申请人提供）：气道平滑肌（ASM）过度收缩和气道狭窄是哮喘的标志性特征。ASM的收缩主要由神经系统调节。在哮喘等气道疾病中，炎症导致ASM的神经调节变得有缺陷，从而促进过度收缩。我们最近建立了一种新型的慢性气道疾病（囊性纤维化，CF）的猪模型，并发现新生CF猪在没有气道感染和炎症的情况下显示出过度收缩的ASM。因此，CF中ASM过度收缩的机制仍然未知。在本申请中，候选人假设ASM的神经调节缺陷导致不依赖于气道炎症的过度收缩。她根据她的工作提出了这一假设，表明CF新生猪中存在几种新的神经系统表型。这些包括轴突密度降低、气道神经支配减少和神经功能下降。候选人提议：1）确定CF猪中ASM的抑制性神经控制（促松弛）是否有缺陷;和2）研究阻断促收缩神经输入是否改善CF猪中的ASM过度收缩。候选人的长期职业目标是成为神经科学和气道疾病研究领域公认的领导者。她计划通过使用猪模型研究ASM的神经调节来推进这两个领域。猪模型的选择特别相关，因为气道解剖学和生理学以及神经系统比传统啮齿动物模型更接近人类。在目前的K99/R 00申请中，候选人将获得智力，专业和技术技能，使她成为一名独立和成功的研究者，专门从事ASM的神经调节。在指导阶段，她将学习ASM生物学，肺切片培养，Ca 2+成像，形态测量学和使用flexiVent的整个动物肺力学。她创建了一个特殊的辅导团队和培训计划，以确保她学习这些技能。此外，候选人将在马约诊所进行正式演讲，参加美国哮喘基金会资助获奖者突破性研究年会，为美国呼吸细胞杂志审查手稿，担任医学生“基于问题的学习”课程的组长，并获得管理预算的重要技能。候选人将利用这些技能在她的独立阶段，以调查酸诱导的气道损伤中ASM的神经调节。这个主题是非常重要的，因为酸化的气道发生在哮喘和酸性pH值有力地激活轴突支配气道。因此，候选人有一个前所未有的机会，阐明神经机制参与ASM过度收缩使用模型与人类疾病直接相关。总之，该奖项将培养候选人成为神经科学和气道疾病研究的领导者，从而推进该领域并改善气道疾病患者的生活。

DESCRIPTION (provided by applicant): Exaggerated airway smooth muscle (ASM) contraction and airway narrowing are hallmark traits of asthma. Contraction of ASM is predominantly regulated by the nervous system. In airway diseases such as asthma, inflammation causes neural regulation of ASM to become defective, thus promoting hypercontraction. We recently generated a novel porcine model of a chronic airway disease (cystic fibrosis, CF), and discovered that newborn CF pigs display hypercontracted ASM in the absence of airway infection and inflammation. Thus, the mechanism of ASM hypercontraction in CF remains unknown. In the current application, the candidate hypothesizes that defective neural regulation of ASM causes hypercontraction independent of airway inflammation. She hypothesizes this based upon her work indicating that there are several novel nervous system phenotypes in newborn pigs with CF. These include reduced axon density, decreased innervation of the airway, and decreased nerve function. The candidate proposes to: 1) determine whether inhibitory neural control (pro-relaxation) of ASM is defective in CF pigs; and 2) investigate whether blocking pro-contractile neural input ameliorates ASM hypercontraction in CF pigs. The candidate's long-term career goal is to become a recognized leader in neuroscience and airway disease research. She plans to advance both fields by examining neural regulation of ASM using porcine models. The selection of the porcine model is particularly relevant because the airway anatomy and physiology, as well as the nervous system, more closely resemble humans than traditional rodent models. In the current K99/R00 application, the candidate will gain intellectual, professional and technical skills that will allo her to become an independent and successful investigator specializing in neural regulation of ASM. During the mentored phase, she will learn ASM biology, lung slice culturing, Ca2+ imaging, morphometry, and whole animal pulmonary mechanics using flexiVent. She has created an exceptional mentoring team and training plan to ensure she learns these skills. In addition, the candidate will give formal presentations at Mayo Clinic, attend the American Asthma Foundation Funding Breakthrough Research Annual Meeting of Awardees, review manuscripts for American Journal of Respiratory Cell, serve as a group leader for a medical students "Problem-Based Learning" course, and attain skills important for managing budgets. The candidate will utilize these skills during her independent phase to investigate neural regulation of ASM in acid-induced airway injury. This topic is highly significant as acidification f the airway occurs in asthma and acidic pH potently activates axons innervating the airway. Hence, the candidate has an unprecedented opportunity to elucidate neural mechanisms involved in ASM hypercontraction using models with direct relevance to human disease. In summary, this award will train the candidate to become a leader in neuroscience and airway disease research, thereby advancing the field and enhancing the lives of people living with airway disease.