Insulin increases nerve-mediated bronchoconstriction in obesity-related asthma

胰岛素增加肥胖相关哮喘中神经介导的支气管收缩

基本信息

批准号：
10587344
负责人：
ALLISON Deborah FRYER
金额：
$ 63.05万
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：
2022-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587344
关键词：
3-Dimensional Acetylcholine Acute Afferent Neurons Animals Anti-Cholinergics Architecture Asthma Bronchoconstriction Bronchodilator Agents Chimeric Proteins Computer Assisted Data Disease Management Epithelium Goals Health Care Costs Hospitalization Human Hyperinsulinism In Vitro Incidence Inhalation Insulin Insulin Receptor Light Link Lung Measures Mediating Medicine Methods Molecular Mus Muscarinic M2 Receptor Muscarinic M3 Receptor Muscle Contraction Nerve Neuronal Dysfunction Neurons Neurotransmitters Obese Mice Obesity Pathway interactions Patients Peripheral Pharmaceutical Preparations Prevalence Prevention Quality of life Rattus Reflex action Research Role Sensory Serotonin Severities Severity of illness Signal Pathway Signal Transduction Smooth Muscle Streptozocin Structure Symptoms Techniques Testing Tissues Trachea Transgenic Mice Treatment Cost Vagotomy Vagus nerve structure afferent nerve airway epithelium airway hyperresponsiveness arm asthmatic cholinergic density effective therapy in vivo evaluation innovation nerve supply neural neuroregulation new therapeutic target novel obese patients obese person obesity treatment obesity-associated asthma optogenetics prevent receptor expression reconstruction respiratory smooth muscle

项目摘要

Project Summary Obesity increases both the incidence and severity of asthma. Obesity-related asthma is associated with more frequent symptom exacerbations and hospitalizations, which respond poorly to current asthma medications leading to increased healthcare costs and decreased quality of life. The molecular mechanisms of obesity-related asthma are yet to be defined, making effective prevention and management of this disease difficult. Parasympathetic and sensory nerves control airway tone and mediate reflex bronchoconstriction. This proposal builds on our previous discoveries that 1) increased insulin, associated with obesity, causes airway hyperreactivity mediated by the vagus nerve in obese rats, 2) that asthma severity is associated with increased density of sensory nerves in the lung, and 3) that obese mice with high levels of insulin have increased reflex bronchoconstriction and increased sensory innervation supplying airway epithelia. Thus, we hypothesize that increased insulin, as seen in obesity, potentiates airway hyperreactivity by changing both sensory and parasympathetic nerves, and that these changes are mediated by insulin receptors on airway nerves. We propose to test whether airway hyperreactivity in obese mice is mediated by increased activation of sensory nerves or parasympathetic nerves or a combination of both, and identify how insulin may change neural control. We will also measure insulin-related changes in airway parasympathetic and sensory nerve structure and density, and changes in neurotransmitter expression and release. Finally, we will identify cell signaling pathways by which insulin promotes sensory innervation and neurotransmitter expression. This project uses cutting edge, innovative techniques developed in our labs, and will significantly increase our understanding of underlying mechanisms by which obese patients with increased insulin are more prone to have asthma with increased severity. The long-term goal of the proposed research is to facilitate identification of novel therapeutic targets for prevention and treatment of obesity-related asthma.

项目概要肥胖会增加哮喘的发病率和严重程度。与肥胖相关的哮喘与更多症状频繁恶化和住院治疗，对当前的哮喘药物反应不佳导致医疗费用增加和生活质量下降。肥胖相关的分子机制哮喘尚未得到定义，使得有效预防和管理这种疾病变得困难。副交感神经和感觉神经控制气道张力并介导反射性支气管收缩。这个提议基于我们之前的发现，1) 与肥胖相关的胰岛素增加会导致气道肥胖大鼠迷走神经介导的高反应性，2) 哮喘严重程度与肺部感觉神经密度增加，3）胰岛素水平高的肥胖小鼠反射性支气管收缩增加，供应气道上皮的感觉神经支配增加。因此，我们假设，如肥胖症中所见，胰岛素增加会通过改变气道过度反应性来增强气道高反应性。感觉神经和副交感神经，这些变化是由气道上的胰岛素受体介导的神经。我们建议测试肥胖小鼠的气道高反应性是否是由增加的激活介导的感觉神经或副交感神经或两者的组合，并确定胰岛素如何改变神经控制。我们还将测量气道副交感神经和感觉神经结构中胰岛素相关的变化和密度，以及神经递质表达和释放的变化。最后，我们将识别细胞信号传导胰岛素促进感觉神经支配和神经递质表达的途径。该项目使用我们实验室开发的尖端创新技术，将显着提高我们的理解胰岛素增加的肥胖患者更容易患哮喘的潜在机制严重程度增加。拟议研究的长期目标是促进新型治疗方法的鉴定预防和治疗肥胖相关哮喘的目标。