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:
- 金额:$ 46.25万
- 依托单位:
- 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:
- 关键词:1-Phosphatidylinositol 3-KinaseAcetylcholineAgonistAnimal ModelAntibodiesAsthmaBiguanidesBindingBlocking AntibodiesBronchoconstrictionClinical TrialsComputer AnalysisCost SavingsDataDietDrug TargetingFat-Restricted DietFunctional disorderGenetic TranscriptionHigh Fat DietHumanHypoglycemic AgentsImage AnalysisIncidenceInflammationInsulinInsulin ReceptorInsulin Signaling PathwayInsulin-Like-Growth Factor I ReceptorLungM2 proteinMeasuresMediatingMessenger RNAMetforminMethodsMitogen-Activated Protein Kinase KinasesModelingMolecularMuscarinic AntagonistsMuscarinic M2 ReceptorMuscarinic M3 ReceptorMuscarinicsNerveNeuronsNon obeseObesityOralPathway interactionsPatientsPeroxisome Proliferator-Activated ReceptorsPharmaceutical PreparationsPhenotypePhysiologicalPioglitazoneProtein IsoformsRattusResearchResistanceRoleSecond Messenger SystemsSeveritiesSignal PathwaySmooth MuscleStreptozocinStructure of parasympathetic ganglionTestingThree-Dimensional ImageTracheaTreatment Costairway hyperresponsivenessasthmaticinnovationmRNA ExpressionmRNA Transcript Degradationneuroblastoma cellnovel strategiespre-clinicalpreventprotein expressionreceptorreceptor expressionreceptor functionreceptor internalizationrespiratory smooth muscleresponse
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ALLISON Deborah FRYER其他文献
ALLISON Deborah FRYER的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ALLISON Deborah FRYER', 18)}}的其他基金
Insulin increases nerve-mediated bronchoconstriction in obesity-related asthma
胰岛素增加肥胖相关哮喘中神经介导的支气管收缩
- 批准号:
10587344 - 财政年份:2022
- 资助金额:
$ 46.25万 - 项目类别:
Oregon Clinical and Translational Research Institute TL1 Program
俄勒冈临床和转化研究所 TL1 项目
- 批准号:
9514380 - 财政年份:2017
- 资助金额:
$ 46.25万 - 项目类别:
Oregon Clinical and Translational Research Institute TL1 Program
俄勒冈临床和转化研究所 TL1 项目
- 批准号:
10197247 - 财政年份:2017
- 资助金额:
$ 46.25万 - 项目类别:
Role of macrophages in organophosphorus pesticide-induced airway hyperreactivity
巨噬细胞在有机磷农药引起的气道高反应性中的作用
- 批准号:
8106431 - 财政年份:2010
- 资助金额:
$ 46.25万 - 项目类别:
Role of macrophages in organophosphorus pesticide-induced airway hyperreactivity
巨噬细胞在有机磷农药引起的气道高反应性中的作用
- 批准号:
8663694 - 财政年份:2010
- 资助金额:
$ 46.25万 - 项目类别:
Role of macrophages in organophosphorus pesticide-induced airway hyperreactivity
巨噬细胞在有机磷农药引起的气道高反应性中的作用
- 批准号:
8462262 - 财政年份:2010
- 资助金额:
$ 46.25万 - 项目类别:
Role of macrophages in organophosphorus pesticide-induced airway hyperreactivity
巨噬细胞在有机磷农药引起的气道高反应性中的作用
- 批准号:
8008728 - 财政年份:2010
- 资助金额:
$ 46.25万 - 项目类别:
Role of macrophages in organophosphorus pesticide-induced airway hyperreactivity
巨噬细胞在有机磷农药引起的气道高反应性中的作用
- 批准号:
8272650 - 财政年份:2010
- 资助金额:
$ 46.25万 - 项目类别:
相似海外基金
Spatiotemporal dynamics of acetylcholine activity in adaptive behaviors and response patterns
适应性行为和反应模式中乙酰胆碱活性的时空动态
- 批准号:
24K10485 - 财政年份:2024
- 资助金额:
$ 46.25万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Structural studies into human muscle nicotinic acetylcholine receptors
人体肌肉烟碱乙酰胆碱受体的结构研究
- 批准号:
MR/Y012623/1 - 财政年份:2024
- 资助金额:
$ 46.25万 - 项目类别:
Research Grant
CRCNS: Acetylcholine and state-dependent neural network reorganization
CRCNS:乙酰胆碱和状态依赖的神经网络重组
- 批准号:
10830050 - 财政年份:2023
- 资助金额:
$ 46.25万 - 项目类别:
Study on biological significance of acetylcholine and the content in food resources
乙酰胆碱的生物学意义及其在食物资源中的含量研究
- 批准号:
23K05090 - 财政年份:2023
- 资助金额:
$ 46.25万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
alpha7 nicotinic acetylcholine receptor allosteric modulation and native structure
α7烟碱乙酰胆碱受体变构调节和天然结构
- 批准号:
10678472 - 财政年份:2023
- 资助金额:
$ 46.25万 - 项目类别:
Diurnal Variation in Acetylcholine Modulation of Dopamine Dynamics Following Chronic Cocaine Intake
慢性可卡因摄入后乙酰胆碱对多巴胺动力学调节的昼夜变化
- 批准号:
10679573 - 财政年份:2023
- 资助金额:
$ 46.25万 - 项目类别:
Striatal Regulation of Cortical Acetylcholine Release
纹状体对皮质乙酰胆碱释放的调节
- 批准号:
10549320 - 财政年份:2022
- 资助金额:
$ 46.25万 - 项目类别:
Differential Nicotinic Acetylcholine Receptor Modulation of Striatal Dopamine Release as a Mechanism Underlying Individual Differences in Drug Acquisition Rates
纹状体多巴胺释放的烟碱乙酰胆碱受体差异调节是药物获取率个体差异的机制
- 批准号:
10553611 - 财政年份:2022
- 资助金额:
$ 46.25万 - 项目类别:
Mechanisms of nicotinic acetylcholine receptor modulation of cocaine reward
烟碱乙酰胆碱受体调节可卡因奖赏的机制
- 批准号:
10672207 - 财政年份:2022
- 资助金额:
$ 46.25万 - 项目类别:
Structural basis of nicotinic acetylcholine receptor gating and toxin inhibition
烟碱乙酰胆碱受体门控和毒素抑制的结构基础
- 批准号:
10848770 - 财政年份:2022
- 资助金额:
$ 46.25万 - 项目类别:














{{item.name}}会员




