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.

项目总结： 肥胖母亲的后代更有可能患上哮喘，尽管确切的分子机制 确定这种关系仍然不清楚。我们最近开发了一种母体肥胖的小鼠模型 概括了在人类后代中看到的代谢异常。尽管它们只接受常规饮食喂养， 肥胖母亲的后代出现高胰岛素血症、呼吸道上皮神经支配和反射性呼吸道 高反应性。副交感神经和感觉神经的变化被认为是导致这种情况的原因 高反应性。我们先前已经报道，高胰岛素血症会降低M2 M受体 对呼吸道副交感神经的作用，导致乙酰胆碱释放增加和增强 副交感神经引起的支气管收缩。也有报道称胰岛素促进轴突生长。 我们之前已经证明，感觉神经支配的增加与疾病的严重程度有关 哮喘患者。基于这些发现，我们假设宫内暴露于母体 肥胖增加了胰岛素中的呼吸道神经支配和随后的呼吸道高反应性- 依赖的态度。在这个项目中，我们将描述呼吸道神经元结构和功能的变化， 神经递质的表达，以及胰岛素在这些变化中的作用，通过测试以下三个特定的 目标。首先，我们将测试母亲肥胖对儿童呼吸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受体在子代神经中的表达。最后，我们将确定胰岛素在呼吸道中的作用。 肥胖母亲后代的高反应性和超神经支配。这个项目使用了尖端技术， 我们实验室开发的创新技术，将显著增加我们对机制的理解 肥胖母亲的成年后代中哮喘的发生率，这将指导我们开发针对特定疾病的新策略 在这一人群中的预防和治疗。