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：
8485619
负责人：
CHARLES W EMALA
金额：
$ 33.68万
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/8485619
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.

描述（由申请人提供）：哮喘是一种慢性气道炎症性疾病，其全球患病率已达到大流行的程度。尽管研究在阐明哮喘的潜在机制方面取得了长足的进步，但近几十年来，针对这种疾病的药理学武器库中新增的内容相对较少。我们实验室取得了多项新发现：（1）3-氨基丁酸A亚型（GABAA）GABAA受体在气道平滑肌细胞上表达，（2）气道中存在内源性GABA能配体-受体系统，（3）内源性气道平滑肌 GABAA 受体的激活可增强放松，(4) GABA（内源性存在于气道中）具有调节气道平滑肌张力的作用， (5)体内GABAA受体激动剂的全身给药减弱了激动剂诱导的气道收缩，并且(6)丙泊酚的部分支气管松弛作用是由气道平滑肌上的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，因此选择性靶向仅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受体亚基组成对气道平滑肌张力调节的重要性。我们之前证明，人气道平滑肌表达有限但高度保守的 GABAA 受体亚基库（包括 14、15、23、32 和 42）。这种有限的亚基库是有利的，因为它可以允许高度选择性地靶向 GABAA ) 气道平滑肌上表达的受体。该提案产生的令人兴奋的初步数据支持了中心假设，即气道上皮是气道 GABA 的重要细胞来源。它通过激酶调节的 GABA 转运蛋白（GAT2 和 GAT4/BGT-1）从上皮细胞释放，作用于气道平滑肌细胞上含有 14 和/或 15 的 GABAA 受体，以促进松弛。这些发现为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提供了一种全新的疗法、一种转化治疗方法和一种新的范例。