Cholinergic hyperinnernation in early life regulates long-term airway reactivity

生命早期的胆碱能过度调节调节长期气道反应性

• 批准号: 9386170
• 负责人: Yan Bai
• 金额: $ 17.22万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-14 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386170
• 关键词: Acetylcholine; Actins; Adult; Adult asthma; Advisory Committees; Affect; Age; Agonist; Allergens; Animal Disease Models; Animal Model; Anti-Cholinergics; Area; Asthma; Biology; Birth; Bronchodilator Agents; Cell Culture Techniques; Cellular Mechanotransduction; Child; Childhood; Childhood Asthma; Chronic; Chronic Obstructive Airway Disease; Clinical; Communities; Development; Development Plans; Disease; Disease Progression; Economic Burden; Environmental Exposure; Evaluation; Event; Exposure to; Family; Fostering; Foundations; Functional disorder; Funding; Gene Expression; Genes; Goals; Health; Human; Infant; Knockout Mice; Lead; Life; Light; Lung; Lung diseases; Maintenance; Mediating; Mentors; Methods; Microarray Analysis; Modeling; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Nature; Nebulizer; Nerve; Obstructive Lung Diseases; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physicians; Play; Precision therapeutics; Predisposition; Prevention; Recovery; Regulation; Research; Respiratory physiology; Risk; Role; Saline; Scientist; Signal Pathway; Signal Transduction; Slice; Small Interfering RNA; Smooth Muscle; Structure; Study Skills; Testing; Therapeutic; Time; Training; Training Programs; United States; United States National Institutes of Health; Up-Regulation; Work; age group; age related; airway hyperresponsiveness; analog; asthmatic; career; career development; cholinergic; environmental change; health economics; in vivo; infancy; insight; knock-down; lung development; mechanotransduction; methacholine; mouse model; muscle physiology; nerve supply; neuroregulation; new therapeutic target; overexpression; pollutant; postnatal; prevent; pup; relating to nervous system; respiratory; respiratory smooth muscle; respiratory virus; tiotropium; treatment strategy

Project Summary: Asthma is a chronic respiratory disease affecting more than 25 million people including 7 million children in the United States and imposing a substantial health and economic burden on patients, their families and the communities. Although asthma may affect all age groups, it most often starts during childhood. Clinical observations have revealed early life environmental insults are associated with increased risk of chronic airway obstructive diseases including asthma. In addition, there is increasing recognition that lung function throughout life is profoundly impacted by respiratory events that occur during the time period of postnatal lung development. These findings highlight the significance of more fully understanding age-related specific airway adaptive changes from environmental exposures in early life. Our work in progress with an early life mouse asthma model has revealed a key role of neural dysregulation of airway smooth muscle (ASM) in the maintenance of airway hyperreactivity (AHR). We found early life allergen exposure induced a unique upregulation of ASM contractility via cholinergic hyperinnervation. This contractile plasticity of ASM in the time window of postnatal airway development played a key role in retaining long term AHR. In contrast, alteration in neural regulation and subsequent long term enhancement of airway contractility was not seen in a murine model of adult asthma. Moreover, microarray analysis of ASM revealed gene expression of CD38 and -actinin1 (ACTN1) was selectively upregulated in P21 ASM following allergen exposure. These genes have established role in the contractile regulation of ASM. We therefore hypothesize that cholinergic stimulation during postnatal development aberrantly activates Ca2+ and ACTN1- mediated pathways in ASM, which in turn causes persistent AHR. We propose to test this hypothesis by 1) identifying the critical time window during which ASM is vulnerable to the aberrant cholinergic regulation; 2) investigating two potential mechanisms underlying cholinergic stimulation induced ASM hypercontractility, ie CD38 mediated Ca2+ signaling pathway and ACTN1 mediated intracellular mechanotransduction; and 3) evaluating the efficacy of anti-cholinergic medication in the prevention of persistent AHR following early life allergen exposure. With the guidance of my mentors, Drs. Xingbin Ai and Bruce Levy, we have developed a five-year training program that includes both tailored didactic and technical training to develop additional skills for study of the regulation of ASM in health and disease. Importantly, this project will be overseen by a scientific career advisory committee with expertise related to key areas of this proposal, including ASM physiology, molecular and developmental lung biology and animal disease models. The proposed career development plan will establish scientific foundations and provide the additional training necessary to achieve my ultimate goal of becoming an independent, NIH-funded physician-scientist studying pulmonary smooth muscle biology and dysregulation in lung diseases.

项目摘要： 哮喘是一种慢性呼吸道疾病，影响超过2500万人，包括700万儿童 在美国，对患者，家人和 社区。尽管哮喘可能会影响所有年龄段，但最常见于童年时期。临床 观察结果表明，早期生活环境侮辱与慢性气道风险增加有关 包括哮喘在内的阻塞性疾病。另外，人们越来越认识到肺部功能 生命受到产后肺发育期间发生的呼吸事件的深远影响。 这些发现突出了更充分了解与年龄相关的特定气道自适应的重要性 早期环境暴露的变化。 我们通过早期生活鼠标模型正在进行的工作揭示了神经元的关键作用 气道平滑肌（ASM）的失调在维持气道高反应性（AHR）中。我们发现 早期过敏原暴露通过胆碱能过度连接引起了ASM收缩性的独特上调。 在产后气道发展的时间窗口中，ASM的收缩性可塑性在 保留长期AHR。相反，神经元调节的改变以及随后的长期增强 在成年哮喘的鼠模型中没有看到气道收缩力。此外，ASM的微阵列分析 在P21 ASM中选择性更新了CD38和-肌动蛋白的基因表达（ACTN1） 过敏原暴露。这些基因在ASM的收缩调节中确立了作用。因此，我们 假设在产后发育过程中胆碱能刺激异常激活Ca2+和actn1- ASM中介导的途径，进而导致持久性AHR。我们建议通过1）检验该假设 确定ASM容易受到异常胆碱能调节的关键时间窗口； 2） 研究了胆碱能模拟的两个潜在机制引起的ASM超额合同，即 CD38介导的Ca2+信号通路和ACTN1介导的细胞内机械转导； 3） 评估抗胆碱能药物在预防早期持续性AHR方面的效率 过敏原暴露。 在我的导师的指导下。 Xingbin AI和Bruce Levy，我们已经开发了五年的培训 计划包括量身定制的教学培训和技术培训，以开发额外的技能来研究 对健康和疾病中ASM的调节。重要的是，该项目将受到科学职业咨询的监督 委员会具有与本提案的关键领域有关的专业知识，包括ASM生理学，分子和 发育性肺部生物学和动物疾病模型。拟议的职业发展计划将建立 科学基础，并提供了实现我成为一个最终目标的额外培训 独立的NIH资助的身体科学家研究肺平滑肌生物学和失调 肺部疾病。