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

项目摘要 哮喘是一个普遍的公共卫生问题，影响着超过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比出生的孩子高得多。 献给患有哮喘的父亲。这种影响不能仅用遗传易感性来解释，这表明 发育期、宫内暴露使儿童易患呼吸道疾病。最近，患有癌症的成年人 哮喘被发现有更多的呼吸道感觉神经支配和更严重的呼吸道阻塞，从而联系 哮喘患者呼吸道感觉神经重构至过度收缩。此外，我们初步的 数据表明，呼吸道神经支配的增加在子宫内发展，这表明哮喘在以后的发展。 生命是在胎儿发育过程中预先设定好的。 为了研究母亲暴露对胎儿发育的影响，我们建立了一种小鼠模型，在该模型中 孕期暴露于屋尘螨变应原的母亲的后代会出现特征性特征 人类哮喘，包括呼吸道高反应性和感觉神经增加。呼吸道高反应性是 定义为对吸入刺激的反应严重夸大的支气管收缩(呼吸道狭窄)， 它是由包括感觉神经和副交感神经在内的反射来调节的。这个项目的目标是 目的是测试感觉神经重塑在成年小鼠过度支气管收缩中的具体作用 这些过敏原的后代接触母亲，并确定感觉神经重塑是否可逆 在已确定的疾病中。 在这项建议中，我将区分感觉神经和副交感神经对呼吸道的贡献 用药理学和外科技术观察成年后代在母体过敏原激发后的反应性，如 以及我开发的一种创新的光遗传方法。由于长时间的呼吸道神经改变 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 (脑源性神经营养因子)，已知可以促进神经生长和存活，在患有脑源性神经营养不良的患者中也会增加 哮喘和暴露于过敏原的母亲的后代。我将测试阻止BDNF是否能逆转 使用我们实验室的新成像技术增加呼吸道感觉神经支配和呼吸道高反应性 量化技术。 综上所述，实现这个项目的目标将：1)确定呼吸道的神经机制 母亲接触变应原后子代的高反应性，2)确定是否已建立神经元 BDNF拮抗后重塑是可逆的，3)可能导致新的治疗方法的发展 儿童哮喘的靶标。

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.