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: 10217685
• 负责人: Yan Bai
• 金额: $ 17.2万
• 依托单位: MASSACHUSETTS GENERAL 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 2023-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217685
• 关键词: Acetylcholine; 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; Risk; Role; Saline; Scientist; Signal Pathway; Signal Transduction; Slice; Small Interfering RNA; Smooth Muscle; Smooth Muscle Actin Staining Method; Smooth Muscle Myocytes; 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; asthma model; asthmatic; career; career development; cholinergic; efficacy evaluation; 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; postnatal development; postnatal period; preservation; prevent; pulmonary function; 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.

项目概要： 哮喘是一种慢性呼吸道疾病，影响着2500多万人，其中包括700万儿童 在美国，这给患者、他们的家人和他们的家人带来了巨大的健康和经济负担。 社区.虽然哮喘可能会影响所有年龄组，但它通常始于儿童时期。临床 观察显示，早期生活环境损伤与慢性气道疾病的风险增加有关。 包括哮喘在内的阻塞性疾病。此外，越来越多的人认识到， 生命受到出生后肺发育期间发生的呼吸事件的深刻影响。 这些发现强调了更全面地了解与年龄相关的特定气道适应性的重要性。 早期生活中暴露于环境的变化。 我们正在进行的小鼠早期哮喘模型的研究揭示了神经元在哮喘中的关键作用。 在维持气道高反应性（AHR）中气道平滑肌（ASM）的失调。我们发现 早期过敏原暴露通过胆碱能神经支配过度诱导ASM收缩性的独特上调。 在出生后气道发育的时间窗内，ASM的这种收缩可塑性在以下方面发挥了关键作用： 保持长期的AHR。相反，神经调节的改变和随后的长期增强， 在成年哮喘的小鼠模型中未观察到气道收缩性。此外，ASM的微阵列分析 结果显示，在P21 ASM中，CD 38和α-辅肌动蛋白1（ACTN 1）的基因表达选择性上调， 过敏原暴露这些基因在ASM的收缩调节中发挥作用。因此我们 假设出生后发育过程中胆碱能刺激异常激活Ca 2+和ACTN 1- 在ASM介导的途径，这反过来又导致持续AHR。我们建议通过以下方式来检验这一假设：1） 确定ASM易受异常胆碱能调节影响的关键时间窗; 2） 研究胆碱能刺激诱导ASM过度收缩的两种潜在机制， CD 38介导的Ca 2+信号通路和ACTN 1介导的细胞内机械转导;和3） 评价抗胆碱能药物预防生命早期持续性AHR的疗效 过敏原暴露 在我的导师艾兴斌博士和布鲁斯利维博士的指导下，我们制定了一项为期五年的培训计划， 该计划包括量身定制的教学和技术培训，以培养更多的技能， 调节ASM在健康和疾病方面的作用。重要的是，这个项目将由一个科学职业顾问监督。 委员会与本提案的关键领域相关的专业知识，包括ASM生理学，分子和 发育肺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，并提供必要的额外培训，以实现我的最终目标，成为一个 独立的，NIH资助的医生，科学家研究肺平滑肌生物学和失调， 肺部疾病