THERAPEUTIC TARGETING OF THE GABAA CHANNEL ON AIRWAY SMOOTH MUSCLE

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很大的进展，但近几十年来，针对这种疾病的药理学研究相对较少。我们实验室有几项新发现：(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)激活内源性气道平滑肌GABAA通道可增强松弛；(4)GABA（内源性存在于气道中）可调节气道平滑肌张力。(5)体内全身给药GABAA通道激动剂可减轻激动剂诱导的气道收缩；(6)部分异丙酚的支气管松弛作用是由GABAA通道介导的气道平滑肌。由于针对GABAA通道的配体/激动剂的药理学特异性是由GABAA亚基组成决定的，因此对特定组织的特定亚基的选择性靶向治疗有望改善治疗。因此，本研究方案的目的是阐明气道平滑肌GABAA通道亚基组成在气道平滑肌张力调节中的重要性。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，而不通过全局激活所有GABAA通道来促进过度镇静。该建议的中心意义在于确定了一种新的治疗机制，以放松刺激物诱导的支气管收缩后狭窄的气道平滑肌。然而，这项工作具有广泛影响哮喘和COPD管理中气道平滑肌张力控制的治疗潜力。在气道平滑肌上表达的GABAA亚基的特异性治疗靶向加上传统的气溶胶给药方法，有望从根本上改善哮喘的药物治疗，这种疾病几十年来在药物治疗方面缺乏实质性的改进。这个奖项将使我获得必要的研究技能，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。

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.