Insulin Modulates Parasympathetic Nerve Control of Lungs

胰岛素调节肺的副交感神经控制

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要：肥胖会增加哮喘的发病率和严重程度，但对分子的了解不完全与肥胖有关的哮喘的机制使其难以预防和治疗这种表型。副交感神经介导了一种气道高反应性的机制。这些神经提供主导气道音调和释放乙酰胆碱（ACH）的自主控制，该乙酰胆碱（ACH）激活M3毒蕈碱受体气道平滑肌，导致收缩和支气管收缩。 ACH释放由抑制性M2控制这些神经上的毒蕈碱受体。因此，气道高反应性来自降低神经元M2 受体功能和随后的ACH释放增加。我们的初步数据表明肥胖是相关的响应副交感神经刺激的支气管收缩增加，神经元M2降低受体功能，即使在没有炎症的情况下，这些作用也是由胰岛素介导的。因此，我们的假设是，肥胖症中观察到的胰岛素增加与气道上的胰岛素受体结合通过降低M2毒蕈碱功能，导致气道高反应性的副交感神经副交感神经（从而增加ACH释放）。我们建议测试胰岛素如何减少M2 受体表达和功能，确定哪种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（饮食，口服抗血糖药物和胰岛素结合抗体）保护M2受体功能并抑制肥胖引起的气道高反应性。这项研究是意义重大，因为它有可能解释为什么肥胖患者增加胰岛素，更容易哮喘并确定新的策略，包括控制胰岛素和M3选择性毒蕈碱拮抗剂，可能治疗与肥胖有关的哮喘。