Insulin Modulates Parasympathetic Nerve Control of Lungs

项目摘要： 肥胖会增加哮喘的发病率和严重程度，但对哮喘分子机制的不完全了解， 肥胖相关哮喘的潜在机制使得难以预防和治疗这种表型。 副交感神经介导气道高反应性的一种机制。这些神经提供了支配性的 自主控制气道紧张和释放乙酰胆碱（ACh），乙酰胆碱激活M3毒蕈碱受体， 气道平滑肌，引起收缩和支气管收缩。ACh释放受抑制性M2控制 这些神经上的毒蕈碱受体因此，气道高反应性是由神经元M2减少引起的。 受体功能和随后增加的ACh释放。我们的初步数据显示肥胖与 对副交感神经刺激的支气管收缩增加，神经元M2减少 受体功能，这些作用是由胰岛素介导的，即使在没有炎症的情况下。所以我们 有一种假说认为，肥胖者体内胰岛素增加，与气道上的胰岛素受体结合， 副交感神经通过降低M2毒蕈碱功能导致气道高反应性， 副交感神经（从而增加ACh释放）。我们建议测试胰岛素如何降低M2 受体表达和功能，确定哪些胰岛素受体和信号通路介导神经元M2 功能障碍和测试是否操纵胰岛素（与饮食，口服降糖药和胰岛素结合 抗体）保护M2受体功能并抑制肥胖诱导的气道高反应性。本研究是 重要的是，它有可能解释为什么胰岛素增加的肥胖患者更容易发生 哮喘和确定新的策略，包括控制胰岛素，和M3选择性毒蕈碱拮抗剂， 可以治疗与肥胖有关的哮喘。

Project Summary: Obesity increases the incidence and severity of asthma, but an incomplete understanding of the molecular mechanisms underlying obesity-related asthma make it difficult prevent and treat this phenotype. Parasympathetic nerves mediate one mechanism of airway hyperreactivity. These nerves provide dominant autonomic control of airway tone and release acetylcholine (ACh), which activates M3 muscarinic receptors on airway smooth muscle, causing contraction and bronchoconstriction. ACh release is controlled by inhibitory M2 muscarinic receptors on these nerves. Thus, airway hyperreactivity results from decreased neuronal M2 receptor function and subsequent increased ACh release. Our preliminary data show that obesity is associated with increased bronchoconstriction in response to parasympathetic nerve stimulation, with reduced neuronal M2 receptor function, and that these effects are mediated by insulin even in the absence of inflammation. Thus, our hypothesis is that increased insulin, as seen in obesity, binds to insulin receptors on airway parasympathetic nerves resulting in airway hyperreactivity by reducing M2 muscarinic function on parasympathetic nerves (thus increasing ACh release). We propose to test how insulin reduces M2 receptor expression and function, identify which insulin receptor and signaling pathways mediate neuronal M2 dysfunction and test whether manipulating insulin (with diet, oral anti-glycemic drugs and with an insulin binding antibody) protects M2 receptor function and inhibits obesity induced airway hyperreactivity. This research is significant because it has the potential to explain why obese patients with increased insulin, are more prone to asthma and identify novel strategies, including control of insulin, and M3 selective muscarinic antagonists, that may treat obesity-related asthma.