Mechanisms of airway hyperresponsiveness in the offspring of obese mothers

肥胖母亲后代气道高反应性的机制

• 批准号: 10646304
• 负责人: Alina Maloyan
• 金额: $ 59.72万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646304
• 关键词: Acetylcholine; Adult; Adult Children; Afferent Neurons; Age; Animals; Architecture; Asthma; Avil; Bronchoconstriction; Child; Chimeric Proteins; Data; Development; Diet; Epithelium; Exposure to; Fasting; Fetus; Glucose Intolerance; High Fat Diet; Human; Hyperinsulinism; Image; Image Analysis; Insulin; Insulin Receptor; Knock-out; Life; Measures; Mediating; Metabolic; Methods; Modeling; Molecular; Mothers; Mus; Muscarinic M2 Receptor; Muscle function; Nerve; Neurites; Neuronal Dysfunction; Neurons; Neurophysiology - biologic function; Neurotransmitters; Obese Mice; Obesity; Optics; Patients; Peripheral; Pharmacology; Physiology; Population; Positioning Attribute; Prevention; Reflex action; Reporting; Research; Role; Sensory; Serotonin; Severity of illness; Smooth Muscle; Structure; Substance P; Techniques; Testing; Thinness; Three-Dimensional Image; Tissues; Umbilical Cord Blood; Vagotomy; Weaning; Woman; afferent nerve; airway epithelium; airway hyperresponsiveness; asthma exacerbation; autonomic nerve; cholinergic; confocal imaging; high risk; in vivo; innovation; maternal obesity; methacholine; microscopic imaging; mouse model; nerve supply; neural; novel; obese mothers; obesity-associated asthma; offspring; optogenetics; pharmacologic; receptor expression; receptor function; respiratory smooth muscle

Project Summary: Offspring of obese mothers are more likely to develop asthma, although the exact molecular mechanisms that determine this relationship remain unclear. We recently have developed a mouse model of maternal obesity that recapitulates metabolic abnormalities seen in offspring seen in humans. Despite being fed solely a regular diet, offspring of obese mother developed hyperinsulinemia, airway epithelium hyperinnervation and reflex airway hyperresponsiveness. Changes in both parasympathetic and sensory nerves are believed to contribute to this hyperresponsiveness. We have previously reported that hyperinsulinemia reduces M2 muscarinic receptor function on airway parasympathetic nerves causing increased acetylcholine release and potentiating parasympathetic nerve-induced bronchoconstriction. It also has been reported that insulin promotes neurite outgrowth, and we have previously shown that increased sensory innervation correlates with disease severity in patients with asthma. Based on these findings, we hypothesize that intrauterine exposure to maternal obesity increases airway innervation and subsequent airway hyperresponsiveness in an insulin- dependent manner. In this project, we will characterize changes in airway neuronal structure and function, neurotransmitter expression, as well as the role of insulin in these changes, by testing the following three specific aims. First, we will test the effect of maternal obesity on airway sensory and parasympathetic nerve function in offspring. Second, we will test the effect of maternal obesity on neuronal architecture, neurotransmitter content and M2 receptor expression in nerves of the offspring. Finally, we will determine the role of insulin in airway hyperresponsiveness and hyperinnervation in the offspring of obese mothers. This project uses cutting edge, innovative techniques developed in our labs and will significantly increase our understanding of the mechanisms of asthma in adult offspring of obese mothers, which will guide us to develop new strategies for specific prevention and treatment in this population.

项目概要： 肥胖母亲的后代更容易患哮喘，尽管确切的分子机制 确定这种关系仍不清楚。我们最近开发了一种孕产妇肥胖小鼠模型 概括了在人类后代中观察到的代谢异常。尽管只吃正常饮食， 肥胖母亲的后代出现高胰岛素血症、气道上皮过度神经支配和反射性气道 过度反应。副交感神经和感觉神经的变化被认为是造成这种情况的原因 过度反应。我们之前报道过高胰岛素血症会降低 M2 毒蕈碱受体 对气道副交感神经的作用导致乙酰胆碱释放增加并增强 副交感神经引起的支气管收缩。据报道，胰岛素可促进神经突 生长，我们之前已经表明，感觉神经支配的增加与疾病的严重程度相关 哮喘患者。基于这些发现，我们假设宫内暴露于母体 肥胖会增加气道神经支配，并随后导致胰岛素的气道高反应性 依赖方式。在这个项目中，我们将描述气道神经元结构和功能的变化， 通过测试以下三个特定的神经递质表达，以及胰岛素在这些变化中的作用 目标。首先，我们将测试母亲肥胖对气道感觉和副交感神经功能的影响。 后代。其次，我们将测试母亲肥胖对神经元结构、神经递质含量的影响 和M2受体在后代神经中的表达。最后，我们将确定胰岛素在气道中的作用 肥胖母亲的后代的过度反应和过度神经支配。该项目采用尖端技术， 我们实验室开发的创新技术将显着增加我们对机制的理解 肥胖母亲成年后代哮喘的发病率，这将指导我们针对特定情况制定新策略 该人群的预防和治疗。