Neural Pathogenesis of Airway Smooth Muscle Defects in Airway Disease

气道疾病中气道平滑肌缺陷的神经发病机制

• 批准号: 8700090
• 负责人: Leah R Reznikov
• 金额: $ 9.72万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700090
• 关键词: ASIC channel; Acids; American; Anatomy; Animals; Anti-Cholinergics; Asthma; Award; Axon; Biology; Birth; Budgets; Bundling; Cells; Chronic; Clinic; Contracts; Cystic Fibrosis; Data; Defect; Detection; Development; Disease; Ensure; Excision; Exhibits; Family suidae; Foundations; Funding; Gene Transfer; Goals; Grant Review; Health; Human; Image; Infection; Inflammation; Journals; Learning; Life; Ligands; Lung; Manuscripts; Mechanics; Mediating; Medical Students; Mentors; Modeling; Muscle Contraction; Myosin Light Chains; Nerve; Nervous system structure; Neurons; Neuropeptides; Neurophysiology - biologic function; Neurosciences; Newborn Infant; Obstructive Lung Diseases; Pathogenesis; Phase; Phenotype; Physiology; Problem-Based Learning; Pulmonary aspiration of gastric contents; Relaxation; Research; Research Personnel; Rodent Model; Slice; Susceptibility Gene; Tachykinin; Technology; Testing; Time; TimeLine; Training; Transcript; Work; airway inflammation; airway obstruction; base; career; cholinergic; cystic fibrosis airway; density; experience; human disease; injured airway; insight; interest; meetings; morphometry; nerve supply; neuromechanism; neuroregulation; novel; overexpression; pollutant; prevent; receptor; relating to nervous system; respiratory; respiratory smooth muscle; skills; therapeutic target; trait

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.

描述（由申请人提供）：夸张的气道平滑肌（ASM）收缩和气道狭窄是哮喘的标志性状。 ASM的收缩主要由神经系统调节。在诸如哮喘之类的气道疾病中，炎症会导致ASM的神经调节变得有缺陷，从而促进过度促进。我们最近产生了一种新型的慢性气道疾病（囊性纤维化，CF）的猪模型，并发现在没有气道感染和炎症的情况下，新生儿CF猪表现出超合同的ASM。因此，CF中ASM超收集的机制仍然未知。在当前的应用中，候选人假设ASM的神经调节有缺陷会导致与气道炎症无关。她根据自己的工作来假设这一点，表明有几种新生儿猪有几种新型神经系统表型。这些包括轴突密度降低，气道神经支配减少以及神经功能降低。候选人提出：1）确定ASM的抑制性神经对照（促释放）是否在CF猪中有缺陷； 2）研究阻止促债神经输入是否可以改善CF猪中的ASM超收获。候选人的长期职业目标是成为神经科学和气道疾病研究的公认领导者。她计划通过使用猪模型检查ASM的神经调节来推进这两个领域。猪模型的选择特别相关，因为与传统的啮齿动物模型相比，气道解剖学和生理以及神经系统更像人类。在当前的K99/R00应用程序中，候选人将获得知识，专业和技术技能，使她成为专门研究ASM神经调节的独立和成功的研究人员。在指导阶段，她将使用Flexivent学习ASM生物学，肺切片培养，Ca2+成像，形态计和整个动物肺力学。她制定了一个卓越的指导团队和培训计划，以确保她学习这些技能。此外，候选人将在Mayo诊所进行正式演讲，参加美国哮喘基金会资助突破性研究年度大会，《美国呼吸细胞杂志评论手稿》，担任医学生“基于问题的学习”的小组负责人。课程，并获得对管理预算重要的技能。候选人将在其独立阶段利用这些技能来研究酸诱导的气道损伤中ASM的神经调节。由于酸化f气道发生在哮喘和酸性pH中，因此该主题非常重要，酸性pH会有效激活轴突的轴突。因此，候选人有一个前所未有的机会，可以使用与人类疾病直接相关的模型来阐明参与ASM超收集的神经机制。总而言之，该奖项将培训候选人成为神经科学和气道疾病研究的领导者，从而促进该领域并改善气道疾病患者的生活。