Regulation of Wound Healing by Opioid Growth Factor

描述（由申请人提供）：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屏障。受伤的皮肤需要及时换肤，以重新建立这种保护功能。皮肤伤口的愈合是一个高度复杂的动态过程，包括收缩、细胞增殖、细胞迁移、细胞外基质的产生和重塑。现在认识到，许多生长物质参与愈合过程，以协调相关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类和小鼠皮肤的稳态和再上皮化。这种天然的阿片肽是自分泌和可能的旁分泌产生的，并与受体相互作用，以一种非细胞毒性和可逆的方式抑制DNA合成，延缓细胞增殖。在这项资助中，我们提议测试OGF-OGFr相互作用参与全层皮肤伤口愈合的假设，以及修复过程可以通过药理学操纵OGFr来调节。实验旨在通过检查多肽和受体的细胞和分子扰动的后果来验证这一假设，以描绘它们对皮肤修复的个体贡献，重点关注细胞增殖、迁移和分化。计划中的研究是一个长期项目的一部分，旨在了解表皮的维护和修复机制。此外，如果我们的假设被证明，内源性OGF系统的操作代表了一种潜在的化疗方式来管理伤口。

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.