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：
8250322
负责人：
CHARLES W EMALA
金额：
$ 34.91万
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 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8250322
关键词：
3-aminobutyric acid Address Aerosols Affect Agonist American Anesthetics Anti-Cholinergics Anti-Inflammatory Agents Anti-inflammatory Asthma Attenuated Bathing Binding Biological Assay Cavia Cell membrane Cell surface Cells Chemosensitization Childhood Chloride Ion Chlorides Chronic Data Disease Effectiveness Electrophysiology (science)Epithelial Cells Epithelium Frequencies Funding GABA Receptor GABA transporter Goals High Pressure Liquid Chromatography Human Immunoblotting Immunohistochemistry In Vitro Inflammatory Knockout Mice Laboratories Ligands Measures Mediating Mediation Membrane Molecular Mus Muscle Tonus Muscle relaxation phase Nerve Neurons Organ Phosphotransferases Prevalence Propofol Receptor Activation Regulation Relative (related person)Relaxation Research Reverse Transcriptase Polymerase Chain Reaction Role Severities Small Interfering RNA Smooth Muscle Smooth Muscle Myocytes Source Specificity Symptoms Synapses System Tachykinin Therapeutic Tissues Trachea airway epithelium airway obstruction constriction gamma-Aminobutyric Acid improved in vivo inhibitor/antagonist laser capture microdissection methacholine novel pandemic disease paracrine prevent public health relevance receptor respiratory smooth muscle transport inhibitor uptake

项目摘要

DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease of the airways whose global prevalence has taken on pandemic proportions. Although research has made great strides in elucidating the underlying mechanisms involved in asthma, in recent decades relatively few new additions have been made to the pharmacological armamentarium for this disease. Our laboratory has made several novel discoveries: (1) that 3-aminobutyric acid subtype A (GABAA) GABAA receptors are expressed on airway smooth muscle cells, (2) that an endogenous GABAergic ligand-receptor system exists in the airway, (3) that activation of endogenous airway smooth muscle GABAA receptors potentiates relaxation, (4) that GABA (endogenously present in the airway) functions to modulate airway smooth muscle tone, (5) that systemic administration of a GABAA receptor agonist administered in vivo attenuates agonist-induced airway constriction and that (6) part of propofol's broncho-relaxant effect is mediated by GABAA receptors on airway smooth muscle. Since pharmacologic specificity of ligands/agonists directed at the GABAA receptor is dictated by GABAA subunit composition, selective targeting of certain subunits restricted to a given tissue hold promise for improved therapy. Therefore, our goal is to elucidate the importance of airway smooth muscle GABAA receptor subunit composition on the modulation of airway smooth muscle tone. We previously demonstrated that human airway smooth muscle expresses a limited, yet highly conserved repertoire of GABAA receptor subunits (including 14, 15, 23, 32 and 42. This limited repertoire of subunits is advantageous, as it may allow for highly selective targeting of GABAA ) receptors expressed on airway smooth muscle. Exciting preliminary data generated for this proposal support the central hypothesis that airway epithelium is an important cellular source for airway GABA. It is released from epithelial cells via kinase- regulated GABA transporters (GAT2 and GAT4/BGT-1) to act upon 14- and/or 15 containing GABAA receptors on airway smooth muscle cells to facilitate relaxation. These findings offer a radical new therapy, a translational therapeutic approach and a novel paradigm for paracrine interactions between airway epithelium and smooth muscle for relaxing airway constriction. PUBLIC HEALTH RELEVANCE: The central hypotheses to be addressed by the studies are that airway epithelium is a cellular source for airway GABA that is released from epithelial cells via kinase-regulated GABA transporters (GAT2 and GAT4/BGT-1). This released GABA can then act upon 14- and/or 15 containing GABAA receptors on airway smooth muscle cells to facilitate relaxation. We plan to identify novel 14 or 15 subunit-selective agonists that can be delivered to airways by aerosol to facilitate airway relaxation. These findings offer a radical new therapy, a translational therapeutic approach and a novel paradigm for paracrine interactions between airway epithelium and smooth muscle for relaxing airway constriction.

描述（由申请人提供）：哮喘是气道的慢性炎症性疾病，其全球流行率占据了大流行比例。尽管研究在阐明哮喘涉及的潜在机制方面取得了长足的进步，但最近几十年来，已经为这种疾病的药理学武术所添加了相对较少的新添加。 Our laboratory has made several novel discoveries: (1) that 3-aminobutyric acid subtype A (GABAA) GABAA receptors are expressed on airway smooth muscle cells, (2) that an endogenous GABAergic ligand-receptor system exists in the airway, (3) that activation of endogenous airway smooth muscle GABAA receptors potentiates relaxation, (4) that GABA (endogenously气道中存在的功能可调节气道平滑肌张力，（5）在体内给药的GABAA受体激动剂的全身给药可减弱激动剂诱导的气道收缩，而（6）丙泊酚的支气管 - 雷神效应的一部分是由GABAA受体介导的GABAA受体对气道平滑肌的GABAA受体介导的。由于针对GABAA受体的配体/激动剂的药理学特异性由GABAA亚基组成决定，因此选择性靶向限于给定组织的某些亚基有望改善治疗。因此，我们的目标是阐明气道平滑肌GABAA受体亚基对气道平滑肌音调的重要性。我们先前证明，人类气道平滑肌表达了GABAA受体亚基的有限但高度保守的曲目（包括14、15、23、32和42。这种有限的亚基库是有利的，因为它可能允许高度选择性地靶向GABAA的GABAA）受体在空中平滑肌上表现出的受体。该提案生成的令人兴奋的初步数据支持了气道上皮是气道GABA的重要细胞来源的中心假设。它通过激酶调节的GABA转运蛋白（GAT2和GAT4/BGT-1）从上皮细胞中释放出来，可在气道平滑肌细胞上作用于14和/或15个含有GABAA受体的14和/或15。这些发现提供了一种根本的新疗法，一种转化治疗方法和一种新型的范式，用于气道上皮和平滑肌之间的旁分泌相互作用，以放松气道收缩。公共卫生相关性：研究要解决的中心假设是气道上皮是通过激酶调节的GABA转运蛋白（GAT2和GAT2和GAT4/BGT-1）从上皮细胞释放的气道GABA的细胞来源。然后，该释放的GABA可以在气道平滑肌细胞上的14和/或15个包含GABAA受体的14和/或15作用，以促进放松。我们计划确定可通过气溶胶将气道放松的新型14或15个亚基选择性激动剂。这些发现提供了一种根本的新疗法，一种转化治疗方法和一种新型的范式，用于气道上皮和平滑肌之间的旁分泌相互作用，以放松气道收缩。