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

项目摘要 哮喘是一种普遍的公共卫生问题，影响着超过10%的美国公民，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 哮喘的父亲。这种效应不能仅仅用遗传易感性来解释，这表明 发育期、子宫内暴露使儿童易患呼吸道疾病。最近，成年人与 哮喘患者气道感觉神经支配增加，气道阻塞加重， 支气管过度收缩与气道感觉神经重塑的关系此外，我们的初步 数据表明，增加气道神经支配的发展在子宫内，这表明哮喘的发展， 生命是在胎儿发育期间预先设定的。 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， 在整个妊娠期暴露于屋尘螨过敏原的母亲的后代发育出特征性特征 包括气道高反应性和增加的感觉神经支配。气道高反应性是 被定义为响应于吸入刺激而极大放大的支气管收缩（气道变窄）， 并且它由包括感觉神经和副交感神经的反射介导。这个项目的目标 目的是检测感觉神经重塑对成年小鼠过度支气管收缩的特异性作用 这些过敏原暴露的母亲的后代，并确定感觉神经重塑是否是可逆的 在既定的疾病。 在这个建议中，我将区分感觉神经和副交感神经对气道的贡献， 使用药理学和外科技术，在母体变应原激发后，成年后代的反应性， 以及我开发的一种创新的光遗传学方法。由于长期的气道神经变化， 哮喘很可能是由神经生长因子维持的，我建议阻断脑源性神经营养因子 脑源性神经营养因子（BDNF），已知其可促进神经生长和存活，并且在患有 哮喘和暴露于过敏原的母亲的后代。我将测试阻断BDNF是否会逆转 增加气道感觉神经支配和气道高反应性，使用我们实验室的新成像， 量化技术。 总之，实现本项目的目标将：1）确定气道的神经机制 在母体变应原暴露后后代中的高反应性，2）鉴定是否建立了神经元 BDNF拮抗作用后，重塑是可逆的，3）可能导致新的治疗方法的开发 儿童哮喘的治疗目标。

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.