The Role of Insulin in Obesity-Related Asthma

胰岛素在肥胖相关哮喘中的作用

• 批准号: 10066651
• 负责人: Gina Nicole Calco
• 金额: $ 4.94万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-04 至 2024-08-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066651
• 关键词: 3-Dimensional; Acetylcholine; Adrenal Cortex Hormones; Adult; Animals; Asthma; Automobile Driving; Blood Vessels; Bronchoconstriction; Clinical; Computer Assisted; Coughing; Data; Development; Diagnosis; Diet; Fluorescence Microscopy; Goals; Growth; Health Care Costs; High Fat Diet; Hyperinsulinism; Image; Imaging Techniques; Incidence; Individual; Inhalation; Injections; Insulin; Insulin Resistance; Investigation; Irritants; Laser Scanning Confocal Microscopy; Length; Link; Lung; Measurement; Measures; Mediating; Metabolic; Methods; Modeling; Morphology; Mus; Nerve; Neurites; Neurogenic Inflammation; Neurons; Neuropeptides; Obese Mice; Obesity; Optics; Pancreas; Peripheral; Pharmaceutical Preparations; Physiology; Prevention; Preventive Intervention; Preventive treatment; Public Health; Quality of life; Reflex action; Research; Risk; Role; Sensory; Serotonin; Severities; Signal Transduction; Streptozocin; Structure; Substance P; Symptoms; Testing; Thinness; Tissues; Vagus nerve structure; afferent nerve; airway epithelium; asthmatic patient; comorbidity; density; digital; in vivo; insight; mouse model; nerve supply; new therapeutic target; novel; obesity development; prevent; quantitative imaging; reconstruction; response; treatment strategy

Project Summary Obesity-related asthma is a significant comorbidity exacerbated by the accelerating global obesity public health crisis. Obese individuals are more than twice as likely to be diagnosed with asthma, and make up the majority of asthmatic patients with severe or difficult-to-treat asthma. These individuals often respond poorly to typical asthma medications, such as corticosteroids, which leads to higher healthcare costs and a substantially reduced quality of life. Although obesity is known to increase the incidence and severity of asthma, the mechanisms driving obesity-related asthma are still not fully defined. There have been a limited number of investigations into mechanisms involving insulin and excessive nerve-mediated bronchoconstriction of the airways, a defining feature of asthma, in obesity-related asthma. Understanding the role of insulin and its effect on the development of obesity-related asthma is critical to targeting preventative interventions and treatments. The goal of this proposal is to elucidate the functional and structural consequences of insulin-mediated changes on reflex bronchoconstriction and airway sensory nerves in the setting of obesity and hyperinsulinemia. The overall hypothesis is that hyperinsulinemia in obesity potentiates airway nerve- mediated reflex bronchoconstriction through increased sensory innervation of the airway epithelium and increased neuronal expression of substance P. This hypothesis will be tested using a mouse model of diet- induced obesity. In vivo lung physiology measurements and novel quantitative imaging techniques will be used to explore the effects of hyperinsulinemia on airway physiology and nerve growth, morphology, and specific neuropeptide expression in obese animals. The specific aims of this proposal are to: (1) Test whether increased insulin potentiates reflex bronchoconstriction in obese mice; and (2) Test whether increased insulin mediates changes in airway sensory nerve structure and neuropeptide expression in obese mice. Achieving these goals will provide insight into how insulin may promote airway nerve-mediated bronchoconstriction and sensory nerve changes in obesity-related asthma and explain why obese individuals are more likely to have asthma. Investigating the mechanisms behind severeand poorly controlled obesity-related asthma will greatly impactthis currently unmet clinical need.

项目概要 肥胖相关哮喘是一种重要的合并症，全球肥胖公共卫生问题的加剧加剧了这种并发症 危机。肥胖者被诊断出患有哮喘的可能性是其两倍以上，并且占大多数 患有严重或难以治疗的哮喘的哮喘患者。这些人通常对典型的反应不佳 哮喘药物，例如皮质类固醇，这会导致更高的医疗费用和显着的 生活质量下降。尽管已知肥胖会增加哮喘的发病率和严重程度，但 肥胖相关哮喘的驱动机制尚未完全明确。已经有数量有限的 研究涉及胰岛素和过度神经介导的支气管收缩的机制 气道是肥胖相关哮喘中哮喘的一个决定性特征。了解胰岛素的作用及其效果 肥胖相关哮喘的发展对于预防性干预和治疗至关重要。 该提案的目标是阐明胰岛素介导的功能和结构后果 肥胖和气道感觉神经反射性支气管收缩和气道感觉神经的变化 高胰岛素血症。总体假设是，肥胖者的高胰岛素血症会增强气道神经- 通过增加气道上皮的感觉神经支配介导反射性支气管收缩 P 物质的神经元表达增加。这一假设将使用饮食小鼠模型进行测试 诱发肥胖。将使用体内肺生理学测量和新颖的定量成像技术 探讨高胰岛素血症对气道生理和神经生长、形态和特异性的影响 肥胖动物中的神经肽表达。该提案的具体目标是： (1) 测试是否 胰岛素增加可增强肥胖小鼠的反射性支气管收缩； (2) 测试胰岛素是否增加 介导肥胖小鼠气道感觉神经结构和神经肽表达的变化。实现 这些目标将深入了解胰岛素如何促进气道神经介导的支气管收缩和 肥胖相关哮喘中的感觉神经变化并解释了为什么肥胖个体更有可能患有 哮喘。研究严重且控制不佳的肥胖相关哮喘背后的机制将极大地帮助我们 影响这一目前尚未满足的临床需求。