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.

项目总结: