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: 10022137
• 负责人: Alexandra Bowman Pincus
• 金额: $ 5.05万
• 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 2023-07-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022137
• 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; asthmatic; density; digital; fetal; fetal programming; imaging modality; improved; in utero; innovation; mouse model; nerve supply; neurotrophic factor; new therapeutic target; novel; offspring; optogenetics; prenatal exposure; prevent; receptor; reconstruction; 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.

项目概要 哮喘是一个普遍的公共卫生问题，影响超过 10% 的美国公民，其中包括 700 万儿童。 患有哮喘的母亲所生的孩子患哮喘的风险明显高于所生的孩子 致患有哮喘的父亲。这种效应不能仅用遗传倾向来解释，这表明存在 发育性的、在子宫内的暴露会使儿童容易患上呼吸道疾病。最近，成年人 研究发现哮喘患者气道感觉神经支配增加，气道阻塞更严重，因此与 气道感觉神经重塑导致哮喘过度支气管收缩。此外，我们初步 数据表明，子宫内气道神经支配增加，这表明哮喘在以后的发展 生命在胎儿发育期间就已被预先编程。 为了研究母体暴露对胎儿发育的影响，我们建立了小鼠模型，其中 在整个怀孕期间接触屋尘螨过敏原的母亲的后代会出现特征性特征 人类哮喘的影响，包括气道过度反应和感觉神经支配增加。气道高反应性是 定义为响应吸入刺激而过度夸张的支气管收缩（气道变窄）， 它是由包括感觉神经和副交感神经在内的反射介导的。该项目的目标 目的是测试成年小鼠感觉神经重塑对支气管过度收缩的具体贡献 这些过敏原暴露母亲的后代，并确定感觉神经重塑是否可逆 在既定疾病中。 在这个提案中，我将区分感觉神经和副交感神经对气道的贡献 使用药理学和手术技术对母体过敏原激发后成年后代的反应性，如 以及我开发的创新光遗传学方法。由于长期持续的气道神经变化 哮喘可能是由神经生长因子维持的，我建议阻断脑源性神经营养因子 （BDNF），众所周知，它可以促进神经生长和存活，并且在患有以下疾病的患者中也会增加 哮喘以及暴露于过敏原的母亲的后代。我将测试阻断 BDNF 是否可以逆转 使用我们实验室的新型成像技术增加气道感觉神经支配和气道高反应性 量化技术。 总而言之，实现该项目的目标将：1）定义气道的神经元机制 母亲过敏原暴露后后代的高反应性，2）确定是否已建立神经元 BDNF 拮抗作用后的重塑是可逆的，并且 3）可能导致新治疗方法的开发 儿童哮喘的目标。