Transmembraneous collagens and matrix metalloproteinases as targets for counterme

跨膜胶原蛋白和基质金属蛋白酶作为对抗靶点

• 批准号: 8545530
• 负责人: MARION K GORDON
• 金额: $ 51.08万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 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/8545530
• 关键词: Adhesions; Alternative Therapies; Angiogenesis Inhibitors; Antibodies; Attenuated; Autophagocytosis; Autophagosome; Back; Basement membrane; Basic Science; Blinking; Bulla; Cells; Centers of Research Excellence; Cleaved cell; Clinical assessments; Collagen; Collagen Type XVII; Combined Modality Therapy; Complex; Cornea; Corneal Injury; Cues; Data; Disease; Doxycycline; Drops; Drug Delivery Systems; Drug Targeting; Enhancers; Enzymes; Epithelial; Epithelial Cells; Exposure to; Extracellular Matrix; Eye; Eyelid structure; FDA approved; Goals; Grant; Healed; Histologic; Hour; Hydrogels; Immunofluorescence Immunologic; Impaired wound healing; Incidence; Injury; Lead; Location; MMP2 gene; MMP9 gene; Matrix Metalloproteinases; Mechlorethamine; Membrane Proteins; Modeling; Mustard; Mustard Gas; Neurodegenerative Disorders; Organ Culture Techniques; Oryctolagus cuniculus; Outcome; Paper; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacy (field); Phosphorylation; Preclinical Drug Evaluation; Procedures; Process; Prodrugs; Publishing; Research; Right-On; Role; Skin; Stromal Cells; Testing; Therapeutic; Time; Tissues; Toxic effect; Transmission Electron Microscopy; Universities; Vesicants; Work; Wound Healing; bevacizumab; corneal epithelium; crosslink; design; drug candidate; drug development; drug testing; healing; improved; in vivo; inhibitor/antagonist; interest; link protein; migration; neovascularization; prevent; protein aggregate; research study; tool

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.

我们研究的总体目标是在芥子损伤后保持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。许多关于芥末的研究都集中在它们对上皮细胞的直接影响。虽然这些细胞具有最终控制权，但它们的细胞外基质是它们生存的关键因素，并具有指导性功能，促进它们的迁移、增殖或分化，这代表了 我们的研究重点。由于暴露于硫芥而发生的基质严重改变，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识别抑制基底膜降解基质金属蛋白酶的药物，特别是 ADAM17/TACE，它可以裂解上皮细胞层和基质细胞层之间的粘附复合物的成分；我们也是 研究自噬在去除发泡剂修饰的基底膜中交联蛋白中的作用。在下一个资助期内，我们还将继续与药理学和药物开发核心以及药物化学和药剂学核心合作进行研究，以进一步开发负载强力霉素的水凝胶作为角膜中潜在的硫芥和氮芥对策。我们的初步数据和发表的论文表明，这些水凝胶在减轻硫芥引起的角膜损伤方面非常有效；需要进行更多的研究来提高它们在兔眼模型中的功效。