miR-203介导的隐丹参酮诱导银屑病表皮细胞凋亡的机制研究

Patients suffer more from psoriasis physically and mentally, but there are not satisfied therapeutic drugs presently. Hyperproliferation, apoptosis missing and aberrant differentiation of epidermal keratinocytes are main alterations in the pathophysiology of psoriasis. We found before that cryptotanshinone had evident proliferation-inhibiting and apoptosis-inducing activities in keratinocytes HaCaT cells, whereas had no effect in normal fibroblasts, which proved the effectiveness and safety of cryptotanshinone. Furthermore, we discovered the elevated miR-203 in psoriasis could be reduced by cryptotanshinone in HaCaT cells, which shed light on the important regulating role of miR-203. We plan to overexpression and/or silence miR-203 in HaCaT cells to confirm positively and negatively the fact that miR-203 takes exact part in modulating the cryptotanshinone effect. SCOS-3 and p63, which were predicted and verified as downstream molecules of miR-203, supply a plausible link between miR-203 and HaCaT apoptosis. In addition, mouse tail test will be introduced to demonstrate the anti-proliferation, apoptosis- and differentiation-inducing activities of cryptotanshinone in vivo, and overexpression miR-203 locally can reduce these effects. This research supplies the laboratory evidences of cryptotanshinone to be a psoriasis candidate drug and miR-203 to be a patent clinical therapeutic target.

银屑病严重危害患者身心健康，目前尚缺乏满意的治疗药物。表皮细胞增殖过度，凋亡减少以及分化异常是银屑病主要的病理改变。本课题组经筛选发现，隐丹参酮具有良好的促进表皮角质形成细胞（HaCaT）凋亡和抑制其增殖的活性，而对正常皮肤成纤维细胞生长无影响，显示了该药的有效性和安全性；进一步研究发现银屑病表皮中上调表达的miR-203，经隐丹参酮诱导可降低表达。本项目拟利用真核转染技术，在细胞中过度/抑制表达miR-203，正反两方面证明它的关键性调控作用；进而预测并证明其下游靶基因p63和SOCS-3是联系miR-203和HaCaT细胞凋亡的重要分子。在此基础上，体内实验采用小鼠尾鳞片模型，局部皮肤过表达miR-203，检测对隐丹参酮所诱导的表皮凋亡、增殖抑制和分化的影响。多层次深入揭示miR-203在隐丹参酮治疗银屑病时所扮演的重要角色，使其成为临床治疗的银屑病的新靶点。

银屑病严重危害患者身心健康，目前尚缺乏满意的治疗药物。表皮细胞增殖过度，凋亡减少以及分化异常是银屑病主要的病理改变。本课题组经筛选发现，隐丹参酮在咪喹莫特诱导的银屑病小鼠动物模型上具有特异性抑制银屑病角质形成细胞增殖的治疗作用。在体外实验同样发现它具有良好的抑制表皮角质形成细胞（HaCaT）增殖以及促进其凋亡的作用，而对正常皮肤成纤维细胞生长无影响，显示了该药的有效性和安全性。鉴于前期结果发现给以隐丹参酮后miR-203变化不明显，我们后续通过microRNAs芯片以及qPCR筛选可以发现隐丹参酮能通过上调miR-187发挥其抑制角质形成细胞增殖和促进其凋亡的效应。而且隐丹参酮上调的miR-187可能通过影响转录因子stat3的磷酸化来发挥其作用。本项目的完成为临床治疗银屑病提供了一个新的治疗药物，并为银屑病的治疗也从表观遗传学的角度提供了一个新靶点。