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。皮肤损伤需要立即进行表面修复，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，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，许多生长物质参与愈合过程以协调所涉及的细胞之间的相互作用。我们已经发现，由[Met 5]-脑啡肽（称为阿片样生长因子，OGF）及其受体（OGFr）组成的内源性阿片样物质系统调节人和小鼠皮肤中的稳态和再上皮化。这种天然阿片肽是自分泌和可能的旁分泌产生的，并与其受体相互作用，以紧张性抑制DNA合成，并以非细胞毒性和可逆的方式延缓细胞增殖。在这项研究中，我们提出了一个假设，即OGF-OGFr的相互作用参与了全层皮肤伤口的愈合，修复过程可以通过操纵OGFr来调节。实验的目的是通过检查肽和受体的细胞和分子扰动的后果来测试这一假设，以描述它们对皮肤修复的各自贡献，重点是细胞增殖、迁移和分化。 计划中的研究是一个长期计划的一部分，旨在了解表皮维护和修复的机制。此外，如果我们的假设得到证实，内源性OGF系统的操作代表了一个潜在的化学治疗方式的伤口管理。

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.