Regulation of Wound Healing by Opioid Growth Factor

说明(申请人提供)：皮肤是人体最大的器官，其主要功能是作为抵御外部环境的保护性屏障。对皮肤的损伤需要立即重新铺设，以便重新建立这种保护功能。皮肤创伤的愈合是一个高度复杂的动态过程，涉及收缩、细胞增殖、细胞迁移、细胞外基质的产生和重塑。现在认识到，许多生长物质参与修复过程，以协调所涉及的细胞之间的相互作用。我们发现，由[Met5]-脑啡肽(称为阿片生长因子，OGF)及其受体(OGFr)组成的内源性阿片系统调节人和小鼠皮肤的动态平衡和再上皮化。这种天然的阿片肽是自分泌的-也可能是旁分泌的-产生并与其受体相互作用，以张力抑制DNA合成，并以非细胞毒性和可逆的方式延缓细胞增殖。在这项授权中，我们建议测试一种假设，即OGF-OGFr的相互作用参与了全层皮肤创伤的愈合，修复过程可以通过药物操作OGFr来调节。实验旨在通过检测多肽和受体的细胞和分子扰动的后果来检验这一假说，以描绘它们对皮肤修复的单独贡献，重点是细胞的增殖、迁移和分化。计划中的研究是一个长期计划的一部分，旨在了解涉及表皮维护和修复的机制。此外，如果我们的假设得到证实，操纵内源性OGF系统代表了一种潜在的治疗伤口的化疗方式。

DESCRIPTION (provided by applicant): The skin is the largest organ of the body and its primary function is to serve as a protective barrier against the external environment. Injury to the skin requires prompt resurfacing in order to re-establish this protective function. Healing of a skin wound is a highly complex, dynamic process involving contraction, cell proliferation, cell migration, production of an extracellular matrix, and remodeling. It is now appreciated that a number of growth substances participate in the healing process to coordinate the interaction between the cells involved. We have discovered that an endogenous opioid system, comprised of [Met5]-enkephalin (termed opioid growth factor, OGF) and its receptor (OGFr), modulates homeostasis and re-epithelialization in human and mouse skin. This native opioid peptide is autocrine- and possibley paracrine-produced and interacts with its receptor to tonically inhibit DNA synthesis, and retard cellular proliferation in a non-cytotoxic and reversible fashion. In this grant we propose to test the hypothesis that OGF-OGFr interactions participate in the healing of a full-thickness skin wound and that the repair process can be modulated by pharmacologically manipulating OGFr. Experiments are designed to test this hypothesis by examining the consequences of cellular and molecular perturbation of the peptide, and of the receptor, in order to delineate their individual contributions to skin repair, with a focus on cellular proliferation, migration, and differentiation. The planned studies are part of a long-range program directed towards understanding the mechanisms involved in maintenance and repair of the epidermis. Furthermore, if our hypothesis is proven, manipulation of the endogenous OGF system represents a potential chemotherapeutic modality for the management of wounds.