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

基本信息

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
项目类别：
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

项目摘要

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，影响超过 2500 万人，其中包括 700 万儿童在美国，给患者及其家人和公众带来沉重的健康和经济负担尽管哮喘可能影响所有年龄段，但它最常见于儿童时期。观察表明，生命早期的环境损害与慢性气道风险增加有关此外，人们越来越认识到肺功能贯穿始终。生命受到出生后肺部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年环境暴露造成的变化。我们正在进行的早期小鼠哮喘模型研究揭示了神经元的关键作用我们发现气道平滑肌（ASM）失调在维持气道高反应性（AHR）中的作用。生命早期的过敏原暴露通过胆碱能过度神经支配诱导了 ASM 收缩性的独特上调。 ASM 在出生后气道发育时间窗口中的这种收缩可塑性在相反，神经调节的改变和随后的长期增强。此外，ASM 的微阵列分析并未在成年哮喘小鼠模型中观察到气道收缩。揭示 CD38 和 α-actinin1 (ACTN1) 的基因表达在 P21 ASM 中选择性上调因此，这些基因在 ASM 的收缩调节中发挥了作用。研究发现，出生后发育过程中的胆碱能刺激会异常激活 Ca2+ 和 ACTN1- ASM 中的介导途径，进而导致持续的 AHR，我们建议通过 1) 来检验这一假设。确定 ASM 易受异常胆碱能调节影响的关键时间窗口 2) 研究胆碱能刺激诱导 ASM 过度收缩的两种潜在机制，即 CD38 介导的 Ca2+ 信号通路和 ACTN1 介导的细胞内机械转导；3) 评估抗胆碱能药物预防生命早期持续性 AHR 的功效过敏原暴露。在我的导师 Xingbin Ai 博士和 Bruce Levy 博士的指导下，我们制定了为期五年的培训计划。计划，包括量身定制的教学和技术培训，以培养学习研究的额外技能重要的是，该项目将受到科学职业咨询的监督。委员会拥有与该提案的关键领域相关的专业知识，包括 ASM 生理学、分子学和拟议的职业发展计划将建立发育性肺生物学和动物疾病模型。科学基础，并提供必要的额外培训，以实现我成为一名由美国国立卫生研究院 (NIH) 资助的独立医师科学家，研究肺平滑肌生物学和失调肺部疾病。