Airway sensory nerve changes in a mouse model of maternal allergen exposure

母体过敏原暴露小鼠模型中气道感觉神经的变化

• 批准号: 10459461
• 负责人: Alexandra Bowman Pincus
• 金额: $ 4.8万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-24 至 2023-06-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459461
• 关键词: 3-Dimensional; Acute; Adult; Adult Children; Affect; Airway Disease; Allergens; Asthma; Brain-Derived Neurotrophic Factor; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Characteristics; Child; Childhood Asthma; Chronic; Computer Assisted; Confocal Microscopy; Contracts; Data; Development; Disease; Dose; Elderly; Exposure to; Fathers; Female; Fetal Development; Fibrinogen; Genetic Predisposition to Disease; Goals; Growth; House Dust Mite Allergens; Human; Image; Inhalation; Irritants; Laboratories; Lead; Length; Link; Lung; Lung diseases; Maternal Exposure; Measures; Mediating; Methodology; Methods; Morphology; Mothers; Mus; Muscarinic Acetylcholine Receptor; Nerve; Nerve Growth Factors; Neurons; Operative Surgical Procedures; Optics; Pathogenesis; Pathway interactions; Patients; Pharmacology; Physiology; Pregnancy; Public Health; Reflex action; Reporting; Risk; Risk Factors; Sensory; Serotonin; Signal Transduction; Stimulus; Structure; Techniques; Testing; Time; Tissues; Vagus nerve structure; Woman; afferent nerve; airway epithelium; airway hyperresponsiveness; airway obstruction; antagonist; asthmatic; density; digital; fetal; fetal programming; imaging modality; improved; in utero; innovation; mouse model; nerve repair; nerve supply; neurotrophic factor; new therapeutic target; novel; offspring; optogenetics; prenatal exposure; prevent; receptor; relating to nervous system; respiratory smooth muscle; response; therapeutic target; 3-Dimensional; Acute; Adult; Adult Children; Affect; Airway Disease; Allergens; Asthma; Brain-Derived Neurotrophic Factor; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Characteristics; Child; Childhood Asthma; Chronic; Computer Assisted; Confocal Microscopy; Contracts; Data; Development; Disease; Dose; Elderly; Exposure to; Fathers; Female; Fetal Development; Fibrinogen; Genetic Predisposition to Disease; Goals; Growth; House Dust Mite Allergens; Human; Image; Inhalation; Irritants; Laboratories; Lead; Length; Link; Lung; Lung diseases; Maternal Exposure; Measures; Mediating; Methodology; Methods; Morphology; Mothers; Mus; Muscarinic Acetylcholine Receptor; Nerve; Nerve Growth Factors; Neurons; Operative Surgical Procedures; Optics; Pathogenesis; Pathway interactions; Patients; Pharmacology; Physiology; Pregnancy; Public Health; Reflex action; Reporting; Risk; Risk Factors; Sensory; Serotonin; Signal Transduction; Stimulus; Structure; Techniques; Testing; Time; Tissues; Vagus nerve structure; Woman; afferent nerve; airway epithelium; airway hyperresponsiveness; airway obstruction; antagonist; asthmatic; density; digital; fetal; fetal programming; imaging modality; improved; in utero; innovation; mouse model; nerve repair; nerve supply; neurotrophic factor; new therapeutic target; novel; offspring; optogenetics; prenatal exposure; prevent; receptor; relating to nervous system; respiratory smooth muscle; response; therapeutic target

Project Summary Asthma is a pervasive public health problem, and affects over 10% of US citizens including 7 million children. Children born to a mother with asthma have a significantly greater risk of developing asthma than children born to fathers with asthma. This effect cannot be explained by genetic predisposition alone, suggesting there are developmental, in utero exposures that predispose children to developing airway disease. Recently, adults with asthma were found to have increased airway sensory innervation and worse airway obstruction, thus linking airway sensory nerve remodeling to excessive bronchoconstriction in asthma. Furthermore, our preliminary data indicate increased airway innervation develops in utero, suggesting that development of asthma in later life is pre-programmed during fetal development. To study the effects of maternal exposures on fetal development, we established a mouse model in which offspring of mothers exposed to house dust mite allergen throughout pregnancy develop characteristic features of human asthma, including airway hyperreactivity and increased sensory innervation. Airway hyperreactivity is defined as greatly exaggerated bronchoconstriction (narrowing of the airways) in response to inhaled stimuli, and it is mediated by a reflex that includes both sensory and parasympathetic nerves. The goal of this project is to test the specific contribution of sensory nerve remodeling to excessive bronchoconstriction in adult mouse offspring of these allergen exposed mothers, and to determine whether sensory nerve remodeling is reversible in established disease. In this proposal, I will distinguish between the contribution of sensory and parasympathetic nerves to airway reactivity in adult offspring after maternal allergen challenge using pharmacological and surgical techniques, as well as an innovative optogenetic approach that I developed. Since long-lasting airway nerve changes in asthma are likely maintained by nerve growth factors, I propose to block brain derived neurotrophic factor (BDNF), which is known to promote nerve growth and survival and which is also increased in patients with asthma and in offspring from mothers exposed to allergen. I will test whether blocking BDNF reverses the increased airway sensory innervation and airway hyperreactivity using our lab's novel imaging and quantification techniques. Taken together, achieving the goals of this project will: 1) define the neuronal mechanism for airway hyperreactivity in offspring following maternal allergen exposure, 2) identify whether established neuronal remodeling is reversible following BDNF antagonism, and 3) may lead to the development of new therapeutic targets for childhood asthma.

项目摘要 哮喘是一个普遍存在的公共卫生问题，影响了包括700万儿童在内的10％的美国公民。 患有哮喘的母亲出生的孩子患哮喘的风险明显比出生的孩子大得多 哮喘的父亲。这种效果不能仅通过遗传易感性来解释 发育性，在子宫暴露中，使儿童易于发展气道疾病。最近，成年人 发现哮喘增加了气道感觉神经支配和较差的气道阻塞，从而连接 气道感觉神经重塑为哮喘中过度的支气管收缩。此外，我们的初步 数据表明，子宫内的气道神经增加了，这表明哮喘的发展稍后 生活在胎儿发育过程中是预先编程的。 为了研究母体暴露对胎儿发育的影响，我们建立了一个小鼠模型，其中 在整个怀孕期间暴露于房屋尘螨过敏原的母亲的后代发展了特征 人类哮喘，包括气道高反应性和增加的感觉神经。气道高反应性是 因吸入刺激而被定义为夸大的支气管收缩（气道变窄）， 它是由包括感觉和副交感神经的反射介导的。这个项目的目标 是测试感觉神经重塑对成年小鼠过度支气管收缩的特定贡献 这些过敏原暴露的母亲的后代，并确定感觉神经重塑是否可逆 在既定疾病中。 在此提案中，我将区分感觉和副交感神经对气道的贡献 使用药理学和外科手术技术，在产妇过敏原挑战后成人后代的反应性，AS 以及我开发的一种创新的光遗传学方法。由于持久的气道神经变化 哮喘很可能是由神经生长因子维持的，我建议阻止脑衍生的神经营养因子 （BDNF），已知可以促进神经的生长和生存，并且在患者中也有所增加 哮喘以及暴露于过敏原的母亲的后代。我将测试阻止BDNF是否逆转 使用实验室的新型成像和 定量技术。 两者合计，实现该项目的目标将：1）定义气道的神经元机制 孕产妇过敏原暴露后后代的过度反应性，2）确定是否已建立神经元 BDNF拮抗后，重塑是可逆的，3）可能会导致新的治疗性发展 儿童哮喘的靶标。