Laminins, metalloproteinases and protection against vesicant-induced skin injury

在这个项目中。Donald Gerecke博士将致力于阐明皮肤中水疱损伤的基本机制，最终目标是确定组织中用于治疗干预和药物开发的新靶点。已知发泡剂使分子烷基化和交联，破坏其生物活性。这可能会对组织的结构和功能造成损害。具体的致病性和分子机制负责水疱剂诱导的皮肤损伤仍不清楚，但细胞内和细胞外的常驻蛋白的修改被认为是关键因素。他的实验室小组发现， 该过程可激活角质形成细胞中的内质网应激途径。他的具体目标是研究内质网应激反应对水疱性损伤的贡献，并评估专门针对这一途径的医学对策。他将确定起疱剂是否改变了层粘连蛋白-332（一种将基底角质形成细胞锚定在基底膜上的关键基质蛋白）与其天然结构伴侣的结合，从而导致基底角质形成细胞从下层真皮中脱离，这一过程可能导致起泡。他还将评估层粘连蛋白-332的烷基化是否影响角质形成细胞的迁移特性，这是伤口修复的关键。最后，计划与药理学和药物 开发核心和药物化学和制药核心，以进一步评价被确定为皮肤中潜在硫芥对策的化合物。他还将继续研究和开发独特的doxycydine负载水凝胶，我们的中心已经证明是有效的对氮芥诱导的皮肤损伤在几个不同的动物模型。

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.