糖尿病视网膜病变中EMCN调控白细胞粘附机制研究

Inflammation is thought to be the common pathway for a variety of pathogenesis of diabetic retinopathy (DR), and DR might be the result of a chronic inflammatory response. The key pathological features include endothelial cell damage, non-perfusion zone formation, retinal ischemia, which is caused by leukocyte adhesion. The main reason of leukocyte adhesion is the imbalance of adhesion factor and anti-adhesion factor. Based on our previous studies on adhesion molecules, this study intends to explore the relevant mechanisms of anti-adhesion molecules in the pathogenesis of DR. Endomucin (EMCN) is an important anti-adhesion molecule of endothelial cell. Our previous research revealed that, the expression of EMCN in retinal vascular endothelial cells is downregulated, and leukocyte adhesion is closely related to the abnormal expression of EMCN in high glucose-treated retinal endothelial cells. However, the mechanism is not yet clear. Our team intends to explore the mechanism of anti-adhesion of leukocyte by EMCN and clarify the regulation mechanism of EMCN expression in diabetic retinopathy and its relationship with the leukocyte adhesion through multiple fields including pathological features, molecular mechanisms and expression regulation. The completion of the project will not only provide important evidence of inflammation and its related molecules involved in the pathogenesis of DR, but also provide a new target for DR prevention and treatment in clinical.

炎症被认为是糖尿病视网膜病变（DR）多种发病机制的共同通路，DR是炎症反应的结果。白细胞粘附增加所导致的内皮细胞受损、无灌注区形成、视网膜缺血缺氧是主要病理特征。白细胞粘附的主要原因在于促粘附因子/抗粘附因子失衡，在前期针对粘附分子研究基础上，本课题拟探讨抗粘附分子在DR发病中的相关机制。内皮粘蛋白（EMCN）是内皮细胞重要抗粘附分子，课题组前期研究发现：糖尿病疾病状态下，视网膜血管内皮细胞EMCN表达下调，且其表达异常与白细胞粘附的关系密切，EMCN表达异常的相关机制尚不明确。课题组拟首先探讨EMCN抗白细胞粘附的相关机制；进一步明确糖尿病疾病状态下EMCN在视网膜血管内皮的表达、表达改变与白细胞粘附的关系；通过“病理特征-分子机制-表达调控”多方面对EMCN表达调控的相关机制进行研究。课题的完成，将为炎症及相关分子参与DR发病机理提供理论依据，也为临床寻找DR防治提供新的干预靶点。

糖尿病视网膜病变（DR）是糖尿病引起的致盲性眼部并发症，以白细胞粘附为始动步骤的炎症被认为是DR多种发病机制的共同通路，继而引起促炎因子、趋化因子等炎性介质的释放并导致血-视网膜屏障（BRB）破坏、视网膜血管阻塞和内皮细胞损伤及坏死等病理改变。血管内皮糖萼结构是血管内皮细胞管腔面的多糖蛋白复合物层，完整的血管内皮糖萼可限制白细胞与内皮细胞的粘附。内皮粘蛋白(EMCN)特异性表达于内皮细胞，是血管内皮糖萼的骨架分子。 本课题通过在视网膜过表达EMCN探讨其对糖尿病引起视网膜血管内皮糖萼损伤、炎症及血管变性的影响。本研究证明了EMCN特异性表达于视网膜血管内皮细胞且在高糖状态下人视网膜微血管内皮细胞及糖尿病大鼠视网膜组织的表达下降。过表达视网膜组织EMCN后可修复糖尿病导致的视网膜内皮细胞糖萼损伤，减少视网膜血管白细胞粘附。进一步的，过表达视网膜组织EMCN后可降低视网膜炎症因子浓度并抑制炎症通路NF-κB的激活，从而减少视网膜血管渗漏及血管内皮紧密连接蛋白的减少，保护了BRB。综上所述，本研究首次证明了EMCN特异性表达于视网膜组织血管内皮细胞且在糖尿病状态下表达下降。过表达EMCN可通过修复血管内皮糖萼，抑制白细胞与视网膜血管内皮细胞的粘附，减轻炎症反应，进而减缓糖尿病引起的视网膜血管病变。本研究丰富了EMCN在DR发病机制中的认知，为DR防治提供了新的靶点。且进一步探究了EMCN在DR发挥抗炎作用的机制，将血管内皮糖萼概念引入到DR的机制研究及防治中来。

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