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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要：肥胖母亲的后代更有可能发展哮喘，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模型在人类中看到的后代中看到的代谢异常。尽管只喂了常规饮食，但肥胖母亲的后代患有高胰岛素血症，气道上皮过度收缩和反射气道反应性过高。据信，副交感神经和感觉神经的变化都会导致反应性过高。我们以前已经报道过高胰岛素血症会降低M2毒蕈碱受体在气道副交感神经上的功能，导致乙酰胆碱释放和增强副交感神经诱导的支气管收缩。还报道了胰岛素促进神经突出生，我们先前已经表明，增加的感觉神经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亲肥胖会增加胰岛素内的气道神经和随后的气道高反应性依赖方式。在这个项目中，我们将表征气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，我们将测试孕产妇肥胖对神经元素，神经递质含量的影响后代神经中的M2受体表达。最后，我们将确定胰岛素在气道中的作用肥胖母亲后代的反应性和过度感染力。该项目使用尖端在我们的实验室中开发的创新技术，将大大提高我们对机制的理解成人肥胖母亲后代哮喘的哮喘，这将指导我们制定新的策略该人群的预防和治疗。