Insulin Modulates Parasympathetic Nerve Control of Lungs

胰岛素调节肺的副交感神经控制

• 批准号: 9233398
• 负责人: ALLISON Deborah FRYER
• 金额: $ 46.25万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233398
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acetylcholine; Agonist; Animal Model; Antibodies; Asthma; Biguanides; Binding; Blocking Antibodies; Bronchoconstriction; Clinical Trials; Computer Analysis; Cost Savings; Data; Diet; Drug Targeting; Fat-Restricted Diet; Functional disorder; Genetic Transcription; High Fat Diet; Human; Hypoglycemic Agents; Image Analysis; Incidence; Inflammation; Insulin; Insulin Receptor; Insulin Signaling Pathway; Insulin-Like-Growth Factor I Receptor; Lung; M2 protein; Measures; Mediating; Messenger RNA; Metformin; Methods; Mitogen-Activated Protein Kinase Kinases; Modeling; Molecular; Muscarinic Antagonists; Muscarinic M2 Receptor; Muscarinic M3 Receptor; Muscarinics; Nerve; Neurons; Non obese; Obesity; Oral; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phenotype; Physiological; Pioglitazone; Protein Isoforms; Rattus; Research; Resistance; Role; Second Messenger Systems; Severities; Signal Pathway; Smooth Muscle; Streptozocin; Structure of parasympathetic ganglion; Testing; Three-Dimensional Image; Trachea; Treatment Cost; airway hyperresponsiveness; asthmatic; innovation; mRNA Expression; mRNA Transcript Degradation; neuroblastoma cell; novel strategies; pre-clinical; prevent; protein expression; receptor; receptor expression; receptor function; receptor internalization; respiratory smooth muscle; response

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.

项目总结： 肥胖会增加哮喘的发病率和严重程度，但对其分子机制的了解不全面 肥胖相关哮喘的潜在机制使预防和治疗这一表型变得困难。 副交感神经介导了呼吸道高反应性的一种机制。这些神经提供了主导 自主控制气道张力和释放乙酰胆碱(ACh)，激活M3 M受体 呼吸道平滑肌，引起收缩和支气管收缩。ACh的释放受抑制的M2控制 这些神经上的毒扁豆碱受体。因此，呼吸道高反应性是由于神经元M2减少所致。 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 副交感神经刺激引起的支气管收缩增加，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。因此，我们的 假设是胰岛素增加，如肥胖所见，与呼吸道上的胰岛素受体结合。 副交感神经通过降低M_2-M受体功能引起呼吸道高反应性 副交感神经(因此增加ACh的释放)。我们建议测试胰岛素是如何降低M2的 受体的表达和功能，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、口服降血糖药物和与胰岛素结合 抗体)保护M2受体功能，抑制肥胖引起的呼吸道高反应性。这项研究是 因为它有可能解释为什么胰岛素升高的肥胖患者更容易患上 哮喘和确定新的策略，包括控制胰岛素和M3选择性M受体拮抗剂， 可以治疗肥胖相关的哮喘。