Regulation of Skin Wound Epithelialization by Galectin-3

描述（由申请人提供）：半乳糖凝集素是一类动物凝集素，由它们对半乳糖苷和一致蛋白序列的亲和力定义。半乳糖凝集素-3是研究最广泛的成员，由多种细胞表达，包括角化细胞和巨噬细胞。我们目前的观点是内源性半乳糖凝集素-3可以通过细胞内机制调节细胞功能，如细胞迁移、生长和凋亡。同时，外源性添加到培养细胞中，半乳糖凝集素-3可以通过与细胞表面聚糖结合诱导跨膜信号转导。现有信息和我们的初步研究表明，半乳糖凝集素-3可能通过其对巨噬细胞和角质形成细胞的影响，对伤口愈合过程有重要贡献：1。利用gal3-/-小鼠对各种炎症模型的研究已经为半乳糖凝集素-3在促进炎症中的作用提供了令人信服的证据。此外，我们最近已经证明内源性半乳糖凝集素-3正调节巨噬细胞的迁移。因此，我们认为内源性半乳糖凝集素-3可以促进伤口愈合过程中单核/巨噬细胞的迁移。我们还提出在皮肤伤口部位添加半乳糖凝集素-3可以吸引单核细胞/巨噬细胞。2. 我们发现内源性半乳糖凝集素-3正向调节角质形成细胞的迁移，并且半乳糖凝集素-3存在于迁移角质形成细胞的前沿。我们还证明了半乳糖凝集素-3在小鼠体内和离体皮肤伤口再上皮化中起重要作用。我们的合作者已经证明内源性半乳糖凝集素-3对角膜创面的再上皮化至关重要，重组半乳糖凝集素-3促进角膜创面修复。拟议的研究旨在明确确定半乳糖凝集素-3在皮肤伤口修复的炎症和再上皮化阶段的作用。我们将讨论半乳糖凝集素-3的内源性和外源性重组蛋白的功能。1：研究半乳糖凝集素-3在皮肤创面愈合过程中巨噬细胞功能中的作用2：研究半乳糖凝集素-3调节角质形成细胞迁移的机制3：研究外源性半乳糖凝集素-3对创面再上皮化的影响这些研究的完成将全面了解内源性半乳糖凝集素-3在皮肤创面愈合的炎症和再上皮化阶段的作用。这些研究也应该揭示外源性添加半乳糖凝集素-3蛋白对皮肤伤口再上皮化的影响。所获得的信息将有助于为研究重组半乳糖凝集素-3作为治疗皮肤伤口的治疗剂奠定基础。表演地点（组织，城市，州）加州大学戴维斯分校，萨克拉门托医疗中心，加利福尼亚州皮肤伤口不愈合是一个主要的医疗问题。该研究项目涉及了解一种叫做半乳糖凝集素-3的蛋白质的功能，它对参与皮肤伤口愈合的不同细胞群的特性进行调节。长期目标是开发治疗皮肤伤口的改进方法。

DESCRIPTION (provided by applicant): Galectins are a family of animal lectins defined by their affinity for ¿-galactosides and consensus protein sequences. Galectin-3 is the most extensively studied member and is expressed by a variety of cells, including keratinocytes and macrophages. Our current view is that endogenous galectin-3 can regulate cellular functions, such as cell migration, growth and apoptosis, through intracellular mechanisms. In the mean time, when added exogenously to cultured cells, galectin-3 can induce transmembrane signal transduction by binding to cell surface glycans. Existing information as well as our preliminary studies suggests that galectin-3 may contribute significantly to the wound healing process through its effects on macrophages and keratinocytes: 1. Studies of various inflammation models using gal3-/- mice have provided convincing evidence for the role of galectin-3 in promotion of inflammation. In addition, we have recently demonstrated that endogenous galectin-3 positively regulates migration of macrophages. Thus, we propose that endogenous galectin-3 can promote migration of monocytes/macrophages during wound healing. We also propose galectin-3 added to skin wound sites can attract monocytes/macrophages. 2. We have found that endogenous galectin-3 positively regulates migration of keratinocytes and galectin-3 is present at the leading edges of migrating keratinocytes. We have also demonstrated that galectin-3 plays an important role in skin wound re-epithelialization in mice both ex vivo and in vivo. Our collaborators have shown that endogenous galectin-3 is essential for re-epithelialization of corneal wounds and recombinant galectin-3 promotes corneal wound repair. The proposed studies are designed to definitively establish the role of galectin-3 in the inflammatory and re-epithelialization phases of skin wound repair. We will address the functions of both galectin-3 present endogenously and exogenously added recombinant protein. 1: Investigation of the role of galectin-3 in the function of macrophages during skin wound healing 2: Investigation of the mechanism by which galectin-3 regulates keratinocyte migration 3: Investigation of the effects of exogenous galectin-3 on wound re-epithelialization The completion of the proposed studies should afford a comprehensive picture of how endogenous galectin-3 functions in the inflammatory and re-epithelialization phases of skin wound healing. The studies should also reveal the effects of exogenously added galectin-3 protein to skin wound re-epithelialization. The information obtained will help set the stage for investigation of recombinant galectin-3 as a therapeutic agent for treatment of skin wounds. PERFORMANCE SITE(S) (organization, city, state) UC Davis, Medical Center Sacramento, CA Skin wounds that do not heal are a major medical problem. This research project deals with understanding of the functions of a protein called galectin-3 in terms of its regulation of properties of different cell populations involved in healing of skin wounds. The long-term goal is to develop improved methods for treatment of skin wounds.