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：
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
项目类别：
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

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。观察结果表明，早期生活环境的侮辱与慢性空气气道的风险增加有关梗阻性疾病还包括哮喘。生命受到发生产后肺发育时期的呼吸事件的深远影响。这些发现突出了一些更完全贾斯和年龄相关的特定气道自适应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的关键作用气道肌肉（ASM）的失调在维持气道高反应性（AHR）中早期生命过敏原暴露通过胆碱能过度保育对ASM收缩性的独特上调。在产后气道开发时间窗口中，ASM的收缩塑料在保留长期AHR。此外，在成人哮喘的鼠模型中没有看到气道收缩力。在P21 ASM中选择性上调CD38和-actinin1（ACTN1）的启示基因表达因此，这些基因在ASM的收缩调节中确立了作用假设在产后发育期间硫蛋白能刺激异常激活Ca2+和Actn1- ASM中的介导途径，这又导致持久性AHR。确定ASM容易受到异常胆碱能调节的关键时间窗口；研究了胆碱能刺激引起的ASM超额合同的两种潜在机制，即 CD38介导的Ca2+信号通路和ACTN1介导的细胞内机械转换；评估抗胆碱能药物在预防早期持续性AHR方面的疗效过敏原暴露。在我的导师的指导下，Drs。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的监管。委员会具有与本提案的关键领域有关的专业知识。发育性肺肺生物学和动物疾病模型。科学基础并提供额外的培训，以实现我的最终目标独立的NIH资助的医师科学家研究肺平滑肌生物学和在肺部疾病。