Prenatal control of offspring airway responsiveness

后代气道反应性的产前控制

• 批准号: 9764662
• 负责人: David B Jacoby
• 金额: $ 59.05万
• 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: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764662
• 关键词: Abbreviations; Adult; Adult Children; Affinity; Amniotic Fluid; Animals; Antibodies; Antigens; Architecture; Asthma; Brain-Derived Neurotrophic Factor; Bronchoconstriction; Childhood Asthma; Development; Eosinophilia; Epithelial; Exposure to; Fetus; Hypersensitivity; IL5 gene; Inflammation Mediators; Interleukin-5; Lead; Life; Lung; Maintenance; Mediating; Modeling; Mothers; Mus; Muscle function; NGFR Protein; NTRK1 gene; Nerve; Nerve Growth Factor Receptors; Nerve Growth Factors; Neurons; Neurotransmitter Receptor; Neurotransmitters; Neurotrophin 3; Physiology; Placenta; Play; Predisposition; Pregnancy; Pregnant Women; Pyroglyphidae; Reflex action; Risk; Risk Factors; Role; Running; Sensory; Smooth Muscle; Structure; Substance P; Substance P Receptor; Testing; Transgenic Organisms; Vagotomy; afferent nerve; airway hyperresponsiveness; airway inflammation; antigen challenge; diphtheria toxin receptor; eosinophil; family genetics; fetal; glial cell-line derived neurotrophic factor; imaging modality; in utero; mouse model; nerve supply; neurotrophic factor; neurotrophin 4; novel; offspring; overexpression; pregnant; prenatal; receptor; receptor expression; relating to nervous system; response

We have recently shown that there is a fundamental difference in airway physiology between wildtype mice born to wildtype mothers and wildtype mice born to IL5 overexpressing mothers or housedust mite (HDM) sensitized mothers. The airways of adult wildtype offspring of these mothers are much more responsive, an effect that requires fetal eosinophilia that develops as the result of maternal IL5 crossing the placenta. Subsequent sensitization and challenge with housedust mite yields much more severe bronchoconstriction. The central hypothesis of this project is that high circulating IL5 during pregnancy induces fetal eosinophilia, and that this causes permanent changes in airway innervation that increase bronchoconstriction. In this project, we propose to determine the mechanisms of airway hyperreactivity in these WT offspring of IL5 transgenic mothers. We will characterize changes in airway nerve structure, transmitters, and receptor expression. We propose three specific aims: SPECIFIC AIM #1: Test the effects of maternal IL5tg and maternal HDM challenge on reflex bronchoconstriction, parasympathetic nerve function, and smooth muscle function. We will determine the role of maternal fetal transfer of IL5 in the maternal HDM challenge model, and test the role of maternal and fetal eosinophilia in these effects. We will also dissect the mechanisms of severe, lethal bronchoconstriction and potentiated airway inflammation when these adult offspring are antigen challenged. SPECIFIC AIM #2: Test whether exposure to IL5 in utero alters the architecture or neurotransmitter content of sensory and parasympathetic nerves. We will use our novel imaging method to determine epithelial and smooth muscle innervation, and to quantify changes in neurotransmitter expression in sensory and parasympathetic nerves. SPECIFIC AIM #3: To determine the role of airway epithelial neurotrophins in 1) heightened response to antigen challenge, 2) severe airway hyperresponsiveness, and 3) maintenance of airway nerve remodeling in adult offspring of IL5tg mothers and in adult offspring of HDM sensitized and challenged mothers. We will extend our preliminary studies of neurotrophin expression to include the different mouse models and treatments in Aim #1, and determine the roles of neurotrophins that are elevated by blocking with antibodies and treating animals with receptor antagonists.

我们最近表明，野生型小鼠之间的气道生理学存在根本差异 由野生型母亲所生，以及由 IL5 过度表达母亲或屋尘螨 (HDM) 所生的野生型小鼠 敏感的妈妈们。这些母亲的成年野生型后代的呼吸道反应更加灵敏， 需要由于母体 IL5 穿过胎盘而产生胎儿嗜酸性粒细胞增多的效应。 随后的过敏和屋尘螨的攻击会产生更严重的支气管收缩。 该项目的中心假设是妊娠期间高循环 IL5 会诱导胎儿 嗜酸性粒细胞增多，这会导致气道神经支配的永久性变化，从而增加 支气管收缩。在这个项目中，我们建议确定气道高反应性的机制 这些IL5转基因母亲的WT后代。我们将描述气道神经结构的变化， 递质和受体表达。我们提出三个具体目标： 具体目标 #1：测试母体 IL5tg 和母体 HDM 挑战对反射的影响 支气管收缩、副交感神经功能和平滑肌功能。我们将确定 母体胎儿转移 IL5 在母体 HDM 激发模型中的作用，并测试母体和胎儿的作用 胎儿嗜酸性粒细胞增多有这些影响。我们还将剖析严重、致命的支气管收缩的机制 当这些成年后代受到抗原攻击时，气道炎症会加剧。 具体目标 #2：测试子宫内暴露于 IL5 是否会改变结构或神经递质含量 感觉神经和副交感神经。我们将使用我们新颖的成像方法来确定上皮细胞和 平滑肌神经支配，并量化感觉和神经递质表达的变化 副交感神经。 具体目标#3：确定气道上皮神经营养因子在以下方面的作用：1) 增强对 抗原激发，2) 严重气道高反应性，3) 维持气道神经重塑 IL5tg 母亲的成年后代和 HDM 致敏和攻击母亲的成年后代。我们将 扩展我们对神经营养蛋白表达的初步研究，以包括不同的小鼠模型和 目标#1 中的治疗，并确定通过抗体阻断而升高的神经营养素的作用 并用受体拮抗剂治疗动物。