THERAPEUTIC TARGETING OF THE GABAA CHANNEL ON AIRWAY SMOOTH MUSCLE

描述（由申请人提供）：哮喘是一种气道慢性炎症性疾病，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，对这种疾病的药理学治疗方法的新增加相对较少。我们的实验室有了几个新的发现：（1）3-氨基丁酸亚型A（GABAA）GABAA通道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通道的激活增强舒张，（4）GABA（内源性存在于气道中）起调节气道平滑肌张力的作用，（5）全身施用体内施用的GABAa通道激动剂减弱激动剂诱导的气道收缩，以及（6）异丙酚的支气管舒张作用的一部分是由气道平滑肌上的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，因此限制于给定组织的某些亚基的选择性靶向有望改善治疗。因此，本研究的目的是阐明气道平滑肌GABAA通道亚基组成对气道平滑肌张力调节的重要性。 所提出的实验有望确定如何利用气道平滑肌GABAA通道亚基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是确定了一种新的治疗机制，以放松收缩的气道平滑肌后刺激诱导支气管收缩。然而，这项工作具有广泛影响哮喘和COPD管理中气道平滑肌张力控制的治疗潜力。特异性靶向气道平滑肌上表达的GABAA亚基的治疗结合传统的气溶胶递送方法，有望从根本上改善哮喘的药理学治疗，哮喘是一种几十年来药物治疗缺乏实质性改善的疾病。 该奖项将使我获得必要的调查技能，实验知识基础和肥沃的合作关系，发展成为一个成功的和独立的临床科学家。 公共卫生相关性：这一建议的中心意义是确定一种新的治疗机制，以放松收缩的气道平滑肌。这项工作将利用麻醉剂的未充分利用的能力，以变构增强内源性气道GABA在气道平滑肌GABAA通道的作用。该建议建立在我们实验室以前的工作基础上，该工作确定了一个有限的GABAA亚基库，该亚基包括在气道平滑肌细胞上表达的功能性GABAA通道。气道平滑肌上表达的GABAA亚基的药理学特异性靶向结合传统的气溶胶递送方法到气道，有望从根本上改善哮喘的药理学治疗，哮喘是一种几十年来药物治疗缺乏实质性改善的疾病。

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.