白三烯B4第二受体（BLT2）调控血管内皮功能参与糖尿病慢性皮肤溃疡的作用机制研究

Chronic diabetic skin ulcer (including diabetic foot) is one of the most severe complications of diabetes mellitus. Due to limited clinical therapy methods and absence of effective medications, diabetic ulcers have a poor prognosis, and 15–27% of all diabetic ulcers lead to the surgical amputation. However, the pathogenesis of diabetic ulcers still remains unknown. To investigate the detailed molecular mechanisms of diabetic ulcers would be a crucial project to treat these intractable skin wounds. Our previous study indicated that activation of BLT2 significantly promote skin wound healing in db/db mice by enhancing skin epidermal keratinocyte migration. However, the role of BLT2 in neovascularization during wound healing remains largely unknown. The aims of the study include: 1) evaluate BLT2 expression levels in skin tissues and vascular endothelial cells; 2) investigate the molecular mechanism(s) by which BLT2 regulates the neovascularization during skin wound healing; 3) animal model study to clarify the involvement of BLT2 in neovascularization and study the therapeutic aspect of BLT2 specific agonist; 4) quantification of arachidonic acid/COX pathway productions by LC-MS/MS. Based on our previous work, this study will investigate the involvement of BLT2 in vascular endothelial cells dysfunction that is implicated in the pathogenesis of diabetes mellitus.

糖尿病慢性皮肤溃疡(糖尿病足)，是糖尿病常见的并发症之一，预后差。而其发病机制仍不明确，因此, 深入研究糖尿病慢性皮肤溃疡的发病机制及临床特点, 寻找新的治疗方法是当今的一项重要课题。我们前期工作中发现，激活BLT2基因能有效促进善糖尿病小鼠皮肤溃疡的愈合，而BLT2在真皮组织层血管修复新生功能中的作用机制仍不明确，本研究拟通过：1）评估BLT2在皮肤真皮层血管内皮细胞内的表达水平；2）研究BLT2调控血管内皮细胞功能参与创伤修复的血管新生过程的分子机制；3）利用基因敲除小鼠和糖尿病小鼠皮肤创伤模型，研究BLT2作为皮肤溃疡治疗新靶向的可行性；4）利用LC-MS/MS技术检测糖尿病足患者皮肤溃疡组织中花生四烯酸代谢产物的水平。进一步明确BLT2参与皮肤创伤愈合血管新生的分子机制，同时探索BLT2受体激动剂在慢性皮肤溃疡治疗中的应用前景，为进一步理解糖尿病慢性皮肤溃疡的发病机制提供理论依据。

糖尿病慢性皮肤溃疡(糖尿病足)，是糖尿病常见的并发症之一，预后差。而其发病机制仍不明确，因此, 深入研究糖尿病慢性皮肤溃疡的发病机制及临床特点, 寻找新的治疗方法是当今的一项重要课题。我们前期工作中发现，激活BLT2基因能有效促进善糖尿病小鼠皮肤溃疡的愈合，而BLT2在真皮组织层血管修复新生功能中的作用机制仍不明确，本研究通过：1）评估BLT2在皮肤真皮层血管内皮细胞内的表达水平，利用人脐静脉内皮细胞培养体系，模拟糖尿病胰岛素抵抗模型，研究BLT2表达水平的变化；2）阐明BLT2调控血管内皮细胞功能参与创伤修复的血管新生过程的分子机制；3）利用基因敲除小鼠和糖尿病小鼠皮肤创伤模型，研究BLT2作为皮肤溃疡治疗新靶向的可行性。本研究进一步明确BLT2参与皮肤创伤愈合血管新生的分子机制，同时探索BLT2受体激动剂在慢性皮肤溃疡治疗中的应用前景，为进一步理解糖尿病慢性皮肤溃疡的发病机制提供理论依据。