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

• 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
• 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

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.

项目摘要 肥胖会增加哮喘的发病率和严重程度。肥胖相关的哮喘与更多 频繁的症状加重和住院治疗，对目前的哮喘药物反应不佳 导致医疗成本增加，生活质量下降。肥胖相关分子机制的研究进展 哮喘的定义尚未确定，这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呼吸道张力，并调节反射性支气管收缩。这项建议 以我们之前的发现为基础：1)与肥胖相关的胰岛素增加会导致呼吸道 由迷走神经介导的肥胖大鼠的高反应性，2)哮喘严重程度与之相关 肺内感觉神经密度增加，以及3)高胰岛素肥胖小鼠有 反射性支气管收缩增加，供应呼吸道上皮的感觉神经增加。 因此，我们假设，胰岛素的增加，如肥胖所见，通过改变 感觉神经和副交感神经，这些变化是由呼吸道上的胰岛素受体介导的 太紧张了。我们建议测试肥胖小鼠的气道高反应性是否是通过增加激活的 感觉神经或副交感神经或两者的组合，并确定胰岛素可能如何改变神经 控制力。我们还将测量与胰岛素相关的呼吸道副交感神经和感觉神经结构的变化。 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 胰岛素促进感觉神经和神经递质表达的途径。本项目使用 我们实验室开发的尖端创新技术，将显著增加我们对 胰岛素升高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的治疗方法的确定 预防和治疗肥胖相关哮喘的目标。