? ? 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) ? ? ?
