Transmembraneous collagens and matrix metalloproteinases as targets for counterme

我们研究的总体目标是保护芥末损伤后角膜上皮基底膜区细胞外基质的完整性，从而为上皮细胞提供恢复的基质。许多关于芥菜的研究都集中在它们对上皮细胞的直接影响上。虽然这些细胞拥有最终的控制权，但它们的细胞外基质是它们生存的关键因素，并起到指导作用，促进它们的迁移、增殖或分化，这代表了 我们研究的重点。硫磺芥末暴露导致基质严重改变，似乎缺乏适当的线索，从而阻止细胞将组织重塑回正常状态。为了克服这个问题，我们开发眼部对策的方法是确定抑制基底膜降解基质金属蛋白酶的药物，特别是ADAM17/TACE，它切割上皮层和间质细胞层之间的黏附复合体的一个组成部分；我们还 研究自噬在去除发泡剂修饰的基底膜中的交联蛋白中的作用。在下一个赠款期间，我们还将继续与药理学和药物开发核心以及药物化学和制药核心合作研究，进一步开发多西胞苷水凝胶，作为潜在的硫芥子气和氮芥子气在角膜中的对策。我们的初步数据和发表的论文表明，这些水凝胶在减轻硫磺芥末引起的角膜损伤方面非常有效；还需要进一步的研究来提高它们在兔眼模型中的疗效。

The overall goal of our research is to preserve the integrity of the extracellular matrix of the corneal epithelial basement membrane zone after mustard injury, thereby providing the epithelial cells a substratum on which to recover. Many studies on mustards have focused on their direct impact on epithelial cells. While these cells have ultimate control, their extracellular matrix is a key factor in their survival, and serves an instructive function, facilitating their migration, proliferation, or differentiation and this represents the focus of our studies. Severely altered matrices, which occur as a result of sulfur mustard exposure, appear to lack the appropriate cues, thereby preventing cells from remodeling the tissue back to a normal state. To overcome this, our approach to developing ocular countermeasures is to identify agents that inhibit basement membrane degrading matrix metalloproteinases, in particular, ADAM17/TACE, which cleaves a component of the adhesion complex between the epithelial and stromal cell layers; we are also investigating the role of autophagy in removing cross-linked proteins in vesicant-modified basement membrane. During the next grant period, we will also continue studies working with the Pharmacology and Drug Development Core and the Medicinal Chemistry and Pharmaceutics Core to further develop doxycydine-loaded hydrogels as potential sulfur mustard and nitrogen mustard countermeasures in the cornea. Our preliminary data and published papers demonstrate that these hydrogels are remarkably effective in mitigating sulfur mustard-induced corneal injury; additional studies are needed to improve their efficacy in the rabbit eye model.