Molecular Mechanisms of Airway Smooth Muscle Relaxation

描述(由申请人提供)： 虽然吸入β-激动剂是治疗和预防哮喘引起的急性支气管痉挛的一线治疗方法，但其作用机制尚不清楚。在这条通向独立的应用之路中，我们提出了一系列假设驱动的实验，以及新方法的发展，以阐明介导气道平滑肌(ASM)松弛的机制。这项拟议的研究将利用小鼠和人类的组织和细胞来探索两种相关药物--β-激动剂和前列腺素E2(PGE2)--介导抑制ASM张力产生的机制。为该奖项的指导阶段和独立阶段提出了两套具体目标。有指导的I期研究将提供重要的新数据，确定在小鼠和人类ASM中钙离子流量调节、收缩和激动剂刺激的信号事件之间的关系。独立的第二阶段研究将通过确定拮抗钙流动和收缩的β-激动剂信号的特定细胞内靶点，以及慢性激动剂治疗如何影响这些靶点的调制，提供对第一阶段结果的更好的机械性洞察。在完成第二阶段研究后，该研究所应具有经验基础和强大的方法，以在ASM生理学和生物学领域进行高度相关的研究。(摘要结束)

DESCRIPTION (provided by applicant): Although inhaled beta-agonist is a first-line therapy for treatment and prophylaxis of acute bronchospasm that occurs with asthma, its mechanisms of action are poorly understood. In this Pathway to Independence application we propose of series of hypothesis-driven experiments, as well as the development of new approaches, to clarify mechanisms mediating airway smooth muscle (ASM) relaxation. The proposed studies will utilize both murine and human tissue and cells to explore mechanisms by which two relevant agents, beta-agonist and prostaglandin E2 (PGE2), mediate inhibition of ASM tension generation. Two sets of Specific Aims for the mentored and independent phases of this award are proposed. Mentored Phase I studies will provide important, new data establishing the relationship between regulation of calcium flux, contraction, and agonist-stimulated signaling events in both murine and human ASM. Independent Phase II studies will provide greater mechanistic insight into the Phase I outcomes by identifying the specific intracellular targets of beta-agonist signaling that antagonize calcium flux and contraction, and how modulation of these targets is influenced with chronic agonist treatment. Upon completion of Phase II studies, the PI should have both an empirical basis and powerful methodologies to pursue highly relevant research in the field of ASM physiology and biology. (End of Abstract)