Directed keratinocyte migration into a wound site is essential for skin repair. Decreased migration results in a chronic wound, of which there are 2,600,000 yearly. Isoproterenol (ISO), a beta-agonist, has a unique effect on keratinocytes, decreasing ERK phosphorylation and inhibiting their migration. This is contrary to reports that show beta2adrenergic receptor (beta2-AR) agonist-mediated activation of ERK in other cell types. The observed beta2-AR inhibition of keratinocyte migration may have wide clinical implications since beta-AR agonists and antagonists are widely used drugs. Asthma affects an estimated 14.2 million Americans, yearly, most of whom are treated with beta2-AR agonists. Nearly 50 million Americans are hypertensive and are also treated commonly by beta-AR antagonists, also known as beta-blockers. Few studies have examined the effects of beta-agonists/antagonists on cutaneous wound healing and the preliminary data suggest that these may profoundly alter the wound healing process. The long-term goal of this work is to understand the mechanisms through which beta-AR agonists modulate migration in human keratinocytes. The hypothesis to be tested is that beta-AR agonists inhibit keratinocyte migration by activating signaling pathways that mediate migration inhibition or by directly interacting with transporters required for cell motility. The initial signaling pathways activated upon ISO binding will be defined and mechanisms of inhibition explored. Interaction between the beta2-AR and specific transporters, known to play a role in migration, will be examined. These investigations will describe the signaling cascades involved in beta-AR agonist-mediated inhibition of keratinocyte migration and wound healing and will hopefully forge the way for more focus on signaling in the field of keratinocyte migration. This might lead to a better understanding of general migration signaling pathways also relevant for embryogenesis, immune defense and cancer progression and provide potentially clinically significant information for the 60-70 million Americans who use beta-AR drugs. Receiving this award will provide me with the financial support and guidance necessary for development into an independent research in the field of Dermatology and will ultimately aid me in obtaining an Adjunct Professor position at UCDavis.
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