Mechanisms of Anesthetic Effects on Tachykinin Induced Airway Tone

麻醉对速激肽诱导气道张力的影响机制

基本信息

批准号：
9394426
负责人：
CHARLES W EMALA
金额：
$ 0.63万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9394426
关键词：
A/J Mouse Absenteeism Adrenergic Receptor Aerosols Agonist Allergens Allergic Anesthetics Asthma Brain Breathing Bronchoconstriction CD28 gene CD3 Antigens Calcineurin Calcium Cells Chemicals Chemosensitization Chlorides Chronic Clinical Clinical effectiveness Collaborations Complex Coupling Data Death Rate Disease Effectiveness Enzymes Eosinophilia Epithelium Event Funding Glutamate Decarboxylase Goals Health Human IL5 gene Immune Impairment In Vitro Inflammation Inflammatory Inhalation Therapy Interleukin-13 Knockout Mice Laboratories Ligands Link Liver Lung Lung Inflammation Lymphocyte Lymphocyte Activation Measures Mediating Mediator of activation protein Medical Membrane Potentials Modeling Molecular Target Mus Muscle Cells Muscle Contraction Muscle Tonus Muscle function Myosin Light Chains Neuroglia Neurons Pathologic Pathway interactions Penetration Perioperative Pharmaceutical Preparations Phosphorylation Physiological Plasma Population Prevention Production Recruitment Activity Relaxation Research Resistance Risk Role Safety Schools Signal Transduction Smooth Muscle Symptoms System T-Lymphocyte Tachykinin Testing Therapeutic Therapeutic Effect Tissues airway hyperresponsiveness asthmatic asthmatic airway cell type clinically relevant conventional therapy cost cytokine desensitization eosinophil experience in vivo lymphocyte proliferation mouse model novel novel therapeutics nuclear factors of activated T-cells public health relevance receptor respiratory smooth muscle therapeutic target voltage

项目摘要

DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease of the airways present in 8% of the US population. It is associated with billions of dollars in health car costs and poorly controlled asthma is the leading medical cause of school absenteeism. Although research has made great strides in elucidating the underlying mechanisms involved in asthma, there have been no new classes of therapeutics for many decades resulting in up to 40% of asthmatics having incompletely controlled symptoms. Components of the most widely used asthma medications, long acting inhaled beta agonists, are associated with an increased death rate from asthma and are currently under FDA-mandated review for long term safety. Our laboratory discovered the expression of GABAA receptors on airway smooth muscle and demonstrated that activation of these classic neuronal receptors could relax airway smooth muscle. We then demonstrated that a complete GABAergic system existed in multiple lung cells including ionotropic GABAA receptors, metabotropic GABAB receptors, the enzymes that synthesize GABA (glutamic acid decarboxylase) and GABA transporters. The GABAA receptors that relax airway smooth muscle contain either an α4 or α5 subunit. Remarkably we have now discovered that key inflammatory cells that mediate allergic lung inflammation also express α4 subunit-containing GABAA channels. In the current proposal we continue our collaboration with a leading GABAA ligand medicinal chemist to identify novel ligands that activate α4 or α5 subunit-containing GABAA channels that will both relax airway smooth muscle and inhibit lung inflammation-the two key pathologic components of asthma. We seek to synthesize derivatives of novel ligands that will be delivered to a murine asthma model by inhalation that would not penetrate the CNS to avoid undesired effects. In aim 1 we will deliver aerosols of GABAA α4 or α5 ligands to asthmatic mice while challenging their airways with a contractile mediator and measure resulting tissue concentrations in plasma, lung, liver and brain. In aim 2 we will test the ability of these GABAA ligands to relax isolated human airway smooth muscle strips and determine the link between their control of membrane potential and intracellular signaling events that control contraction. In aim 3 we will utilize mice lacking GABAA α4 subunits to demonstrate the critical role of GABAA α4 receptors in allergic lung inflammation. We will demonstrate the role of GABAA α4 receptors in regulating membrane potential and lymphocyte activation and proliferation. These approaches offer a radical new therapy, a translational therapeutic approach and a novel paradigm for targeting two key components of asthma; inflammation and airway smooth muscle hyperresponsiveness.

描述（由适用提供）：哮喘是美国8％人口中存在的气道的一种慢性炎症性疾病。它与数十亿美元的保健汽车成本有关，控制哮喘是学校缺勤的主要医疗原因。尽管研究在阐明哮喘涉及的基本机制方面取得了长足的进步，但数十年来，没有新的治疗方法，导致多达40％的哮喘患者没有完全控制症状。使用最广泛使用的哮喘药物的组成部分，长期表演的遗传性β激动剂，与哮喘的死亡率提高有关，目前正在接受FDA的长期安全审查。我们的实验室在气道平滑肌上发现了GABAA受体的表达，并证明这些经典神经元受体的激活可以放松气道平滑肌。然后，我们证明了多个肺部细胞中存在一个完整的GABA能系统，包括离子GABAA受体，代谢性GABAB受体，合成GABA（谷氨酸脱羧酶）和GABA转运蛋白的酶。放松气道平滑肌的GABAA受体包含α4或α5亚基。值得注意的是，我们现在发现介导过敏性肺注射的关键炎症细胞也表达含α4亚基的GABAA通道。在当前的建议中，我们继续与领先的GABAA配体医学化学家合作，以确定激活含α4或α5亚基GABAA通道的新型配体，这些配体将放松气道平滑肌和抑制肺部感染 - 哮喘的两个关键病理学成分。 We seek to synthesize derivatives of novel ligands that will be delivered to a murine asthma model by inhalation that In aim 1 we will deliver aerosols of GABAA α4 or α5 ligands to asthmatic mice while challenging their airways with a contractile mediator and measure resulting tissue concentrations in plasma, lung, liver and brain.在AIM 2中，我们将测试这些GABAA配体放松孤立的人类气道平滑肌条的能力，并确定其控制膜电位与控制收缩的细胞内信号传导事件之间的联系。在AIM 3中，我们将利用缺乏GABAAα4亚基的小鼠来证明GABAAα4受体在过敏性肺注射中的关键作用。我们将展示GABAAα4受体在确定膜电位和淋巴细胞激活和增殖中的作用。这些方法提供了一种根本的新疗法，一种翻译的治疗方法和一种针对哮喘的两个关键组成部分的新型范式。注射和气道平滑肌过度反应性。