Laminins, metalloproteinases and protection against vesicant-induced skin injury

层粘连蛋白、金属蛋白酶和针对疱疹引起的皮肤损伤的保护

基本信息

批准号：
8743068
负责人：
DONALD R GERECKE
金额：
$ 73.62万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-28 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8743068
关键词：
Adhesions Affect Alkylating Agents Alkylation Animal Model Apoptosis Basement membrane Binding Biological Bolus Infusion Bulla Burn injury Cell Surface Receptors Cell Survival Cells Centers of Research Excellence Chemicals Collagen Complex Cream DNA-protein crosslink Dermal Dermis Drug Delivery Systems Epidermis Epithelial Epithelial Cells Exudate Film Gel Generations Genes Goals Grant Hour Hydration status Hydrogels In Vitro Inbred HRS Mice Inflammation Injury Integrins Laboratories Laminin Lead Ligands Liquid substance Location Mechlorethamine Mediating Medical Metalloproteases Modeling Modification Molecular Molecular Chaperones Mustard Mustard Gas Ointments Pathway interactions Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacy (field)Powder dose form Process Property Proteins Research Project Grants Skin Sterile coverings Structure Sulfides System Testing Therapeutic Intervention Tissues Universities Vesicants Work Wound Healing base biological adaptation to stress cell motility chemical threat crosslink drug development drug testing endoplasmic reticulum stress ethylamine extracellular injured keratinocyte migration mouse model particle prevent programs protein misfolding protein protein interaction protein structure receptor research and development therapy development wound

项目摘要

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.

在这个项目中。唐纳德·格雷克（Donald Gerecke）博士将努力阐明皮肤中囊泡损伤的基本机制，其最终目的是确定组织中的新靶标进行治疗干预和药物开发。囊泡剂是烷基化和交联成分子破坏其生物学活性的已知。这可能会损害组织的结构和功能。负责囊泡诱导的皮肤损伤的特定病原和分子机制尚不清楚，但细胞内和细胞外驻留蛋白的修饰被认为是关键因素。他的实验室小组发现该过程可以激活角质形成细胞中的内质网应激途径。他的具体目的是检查内质网应激对囊泡损伤的贡献，并评估专门针对该途径的医学对策。他将确定囊泡是否会改变层粘连蛋白-332（一种临界基质蛋白，将基部角质形成细胞固定在基底膜上，与其自然结构伴侣的自然结构伴侣脱离，导致基础角质形成细胞脱离基础角色，从而导致底层模子，从而导致泡沫。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，角质形成细胞是伤口修复的过程键。最后，计划是使用药理学和药物发育核心以及药物化学和药物核心，以进一步评估被鉴定为皮肤中潜在硫芥末对策的化合物。他还将通过独特的多西环凝胶继续进行研究和开发工作，在几种不同的动物模型中，我们的中心已证明我们中心已证明对氮芥末诱导的皮肤损伤有效。