Molecular Mechanisms of Airway Smooth Muscle Relaxation

虽然吸入性β受体激动剂是治疗和预防急性支气管痉挛的一线疗法， 但其作用机制尚不清楚。在这条通往独立的道路上 应用我们提出的一系列假设驱动的实验，以及新的发展， 方法，阐明介导气道平滑肌（ASM）松弛的机制。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的作用机制， β-激动剂和前列腺素E2（PGE 2）介导ASM张力产生的抑制。两套 本奖项的指导和独立阶段的具体目标提出。指导阶段I 这些研究将提供重要的新数据， 收缩和激动剂刺激的信号传导事件。独立二期 研究将通过识别特定的 拮抗钙流和收缩的β-激动剂信号传导的细胞内靶点，以及如何 这些靶点的调节受到慢性激动剂治疗的影响。第二阶段完成后 研究，PI应该有一个实证基础和强大的方法来追求高度相关 ASM生理学和生物学领域的研究。

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, newdata 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.