THERAPEUTIC TARGETING OF THE GABAA CHANNEL ON AIRWAY SMOOTH MUSCLE

GABAA 通道对气道平滑肌的治疗靶向

• 批准号: 8120856
• 负责人: George Gallos
• 金额: $ 12.57万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120856
• 关键词: 3-aminobutyric acid; Aerosols; Agonist; Airway Resistance; Aminobutyric Acids; Anesthetics; Asthma; Attenuated; Award; Biological Assay; Bronchoconstriction; Calcium; Cells; Chronic; Chronic Obstructive Airway Disease; Coupled; Disease; Dyes; Genetic; Goals; Heterogeneity; Human; Human Engineering; In Vitro; Inflammatory; Intravenous Anesthetics; Irritants; Knockout Mice; Laboratories; Ligands; Mediating; Membrane; Membrane Potentials; Methods; Mus; Muscarinics; Muscle Tonus; Pharmacotherapy; Prevalence; Propofol; Relative (related person); Relaxation; Research; Research Proposals; Scientist; Sedation procedure; Smooth Muscle Myocytes; Specificity; System; Therapeutic; Tissues; Work; constriction; gamma-Aminobutyric Acid; improved; in vivo; knowledge base; methacholine; novel; novel therapeutics; pandemic disease; patch clamp; public health relevance; receptor; release of sequestered calcium ion into cytoplasm; research study; respiratory smooth muscle; skills; therapeutic target

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 channels 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 channels potentiates relaxation, (4) that GABA (endogenously present in the airway) functions to modulate airway smooth muscle tone, (5) that systemic administration of a GABAA channel agonist administered in vivo attenuates agonist-induced airway constriction and that (6) part of propofol's broncho-relaxant effect is mediated by GABAA channels on airway smooth muscle. Since pharmacologic specificity of ligands/agonists directed at the GABAA channel is dictated by GABAA subunit composition, selective targeting of certain subunits restricted to a given tissue hold promise for improved therapy. Therefore, the goal of this research proposal is to elucidate the importance of airway smooth muscle GABAA channel subunit composition on the modulation of airway smooth muscle tone. The proposed experiments hold promise for determining how airway smooth muscle GABAA channel subunit heterogeneity can be harnessed to optimize relaxation of airway smooth muscle without promoting excessive sedation by globally activating all GABAA channels. The central significance of this proposal is the identification of a novel therapeutic mechanism to relax constricted airway smooth muscle following irritant induced bronchoconstriction. However, this work has the therapeutic potential to broadly impact the control of airway smooth muscle tone in the management of asthma and COPD. The specific therapeutic targeting of GABAA subunits expressed on airway smooth muscle coupled with traditional aerosol delivery methods to the airway, holds promise for a fundamental improvement in the pharmacologic therapy of asthma, a disease lacking in substantial improvements in drug therapy for several decades. This award will allow me to obtain the necessary investigational skills, experimental knowledge base, and fertile collaborative relationships to develop into a successful and independent clinician scientist. PUBLIC HEALTH RELEVANCE: The central significance of this proposal is the identification of a novel therapeutic mechanism to relax constricted airway smooth muscle. This work will harness the underutilized ability of anesthetics to allosterically enhance endogenous airway GABA effects at the airway smooth muscle GABAA channel. This proposal builds upon previous work from our laboratory identifying a limited repertoire of GABAA subunits comprising functional GABAA channels expressed on airway smooth muscle cells. The pharmacologic specific targeting of GABAA subunits expressed on airway smooth muscle coupled with traditional aerosol delivery methods to the airway, holds promise for a fundamental improvement in pharmacologic therapy of asthma, a disease lacking in substantial improvements in drug therapy for several decades.

描述(申请人提供)：哮喘是一种慢性呼吸道炎症性疾病，其全球流行率已达到大流行的比例。虽然研究在阐明哮喘的潜在机制方面取得了很大进展，但近几十年来，治疗这种疾病的药理工具相对较少。我们的实验室有几项新发现：(1)3-氨基丁酸A亚型(GABAA)GABAA通道表达于气道平滑肌细胞上；(2)内源性GABAA能配体-受体系统存在于气道中；(3)激活内源性气道平滑肌GABAA通道可增强松弛；(4)GABA(内源性存在于气道)具有调节气道平滑肌张力的功能；(5)全身应用GABAA通道激动剂可减弱激动剂诱导的气道收缩；(6)异丙酚的部分支气管松弛作用是通过GABAA通道介导的。由于针对GABAA通道的配体/激动剂的药理学特异性由GABAA亚基组成决定，选择性靶向特定的亚基限制在给定的组织中有望改善治疗。因此，本研究的目的是阐明气道平滑肌GABAA通道亚单位组成在调节气道平滑肌张力中的重要性。拟议的实验有望确定如何利用气道平滑肌GABAA通道亚单位的异质性来优化气道平滑肌的松弛，而不会通过全局激活所有GABAA通道来促进过度镇静。这一建议的中心意义在于确定了一种新的治疗机制，以松弛刺激性诱导的支气管收缩后狭窄的气道平滑肌。然而，这项工作具有广泛的治疗潜力，可以在哮喘和慢性阻塞性肺疾病的治疗中影响对气道平滑肌张力的控制。针对气道平滑肌表达的GABAA亚单位的特异性治疗靶向与传统的气雾剂给药方法相结合，有望从根本上改善哮喘的药物治疗，哮喘是一种几十年来缺乏实质性药物治疗的疾病。这一奖项将使我获得必要的研究技能、实验知识基础和丰富的合作关系，以发展成为一名成功和独立的临床科学家。 公共卫生相关性：这项建议的中心意义是确定了一种新的治疗机制，以松弛狭窄的气道平滑肌。这项工作将利用麻醉药未被充分利用的能力来变构增强内源性气道GABA在气道平滑肌GABAA通道上的作用。这项建议建立在我们实验室之前的工作基础上，确定了有限的GABAA亚基组成的功能GABAA通道，表达在呼吸道平滑肌细胞上。针对气道平滑肌表达的GABAA亚单位的药理学特异性靶向与传统的气雾剂给药方法相结合，有望从根本上改善哮喘的药物治疗，哮喘是一种几十年来缺乏实质性药物治疗的疾病。