Laminins, metalloproteinases and protection against vesicant-induced skin injury

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In this project. Dr. Donald Gerecke will lead an effort to elucidate basic mechanisms of vesicant damage in the skin with the ultimate goal of identifying new targets in the tissue for therapeutic intervention and drug development. Vesicants are known to alkylate and crosslink molecules disrupting their biological activity. This can cause damage to the structure and function of tissues. The specific pathogenic and molecular mechanisms responsible for vesicant-induced skin injury remain unclear, but modifications of both intracellular and extracellular resident proteins are considered to be key factors. His laboratory group has discovered that this process can activate the endoplasmic reticulum stress pathways in keratinocytes. His specific aims are to examine the contribution of the endoplasmic reticulum stress response to vesicant injury and evaluate medical countermeasures specifically targeting this pathway. He will determine if vesicants alter the binding of laminin-332, a critical matrix protein which anchors basal keratinocytes to the basement membrane, to its natural structural partners causing detachment of the basal keratinocytes from the underlying dermis, a process that can result in blistering. He will also assess whether alkylation of laminin-332 affects the migration properties of keratinocytes, a process key for wound repair. Finally, plans are to work with the Pharmacology and Drug Development Core and the Medicinal Chemistry and Pharmaceutics Core to further evaluate compounds identified as potential sulfur mustard countermeasures in the skin. He will also continue research and development efforts with unique doxycydine-loaded hydrogels that our Center has shown to be effective against nitrogen mustard-induced skin injury in several different animal models.