SK channel antagonists as novel bronchodilators for asthma

描述（由申请方提供）：本提案的长期目标是了解气道平滑肌中钙信号通路的作用机制，以确定临床新型支气管扩张剂。这项建议的近期目标有两个。这项研究将提供一种新的支气管扩张剂UCL 1684如何调节SK通道并导致气道平滑肌松弛的理解（在细胞水平上）。本研究将通过钙成像和气道平滑肌细胞电生理学研究来确定SR SK钾通道影响肌浆网和胞浆钙负荷、ASM细胞兴奋性和收缩性的机制。其次，该研究将在哮喘动物模型和U2激动剂快速耐受模型中研究UCL 1684作为体内支气管扩张剂的功效。该方法将使用整体动物体积描记法和哮喘小鼠的强迫振荡技术来分别评估UCL 1684对气道严重程度和气道阻力的影响。此外，实验将检查UCL 1684对哮喘期间重塑的影响，特别强调其对气道肌肉重塑的影响。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to understand the mechanism of action of calcium signaling pathways in airway smooth muscle in order to identify novel bronchodilators for the clinic. The immediate goals for this proposal are twofold. The research will provide an understanding (at the cellular level) of how a novel bronchodilator, UCL 1684, modulates SK channels and causes airway smooth muscle relaxation. The research will determine the mechanism by which SR SK potassium channels affect sarcoplasmic reticulum and cytosolic calcium load, excitability and contractility of ASM cells using calcium imaging and electrophysiology of airway smooth muscle cells. Second, the research will investigate UCL 1684 efficacy as a bronchodilator in vivo in animal models of asthma and models of ¿2 agonist tachyphylaxis. The approach will be to use whole animal plethysmography, and the forced oscillation techniques on asthmatic mice to evaluate UCL 1684 effects on airway severity and airway resistance, respectively. In addition, the experiments will examine UCL1684 effects on remodeling during asthma with a particular emphasis on its effects on airway muscle remodeling.