Insulin increases nerve-mediated bronchoconstriction in obesity-related asthma

项目摘要 肥胖会增加哮喘的发病率和严重程度。肥胖相关性哮喘与更多 频繁的症状加重和住院，对目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 哮喘尚未被定义，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。这项建议 建立在我们以前的发现上，1）与肥胖相关的胰岛素增加， 肥胖大鼠迷走神经介导的高反应性，2）哮喘严重程度与 肺中感觉神经密度增加，3）胰岛素水平高的肥胖小鼠 增加反射性支气管收缩和增加供应气道上皮的感觉神经支配。 因此，我们假设肥胖者胰岛素增加，通过改变气道高反应性， 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气道高反应性是否是由 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元的功能。 控制我们还将测量胰岛素相关的气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支配和神经递质表达的途径。本项目采用 尖端的，创新的技术在我们的实验室开发，并将大大提高我们的理解， 胰岛素增加的肥胖患者更容易患哮喘， 增加了严重性。拟议研究的长期目标是促进新的治疗方法的鉴定。 肥胖相关性哮喘的防治目标。

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.