CD146在系统性硬化症发展中的作用机制研究

Systemic sclerosis (SSc) is a chronic disease of connective tissues. The pathological characteristics of SSc involve inflammatory responses and fibrosis in the skin and internal organs. Currently, effective strategies for SSc treatment are not available due to the lack of efficient targets and agents. Therefore, it is urgent to identify novel therapeutic strategies for treating SSc. .Our research has been focusing on pathogenesis of connective tissue disease as long-term studies. We found that CD146, a member of the immunoglobulin superfamily, up regulated on fibroblast and endothelial cells in SSc tissues. Recently, increasing evidence suggested that CD146 plays an important role in inflammatory diseases. Anti-CD146 antibody has a desirable effect on several autoimmune disease models. Therefore, we speculate that CD146 may play an important role in the inflammation and fibrosis in the progression of SSc. In this study, we will first investigate the correlation between CD146 expression and SSc disease activation. Then, we will study the effect of anti-CD146 antibody on Blemycin induced skin fibrosis model. Lastly, we will explore the role of CD146 on fibroblast proliferation, migration and fibrotic genes expression. Our findings will explore the role of CD146 in the pathogenesis of skin fibrosis and may provide an efficient therapeutic target for SSc treatment.

系统性硬化症（systemic sclerosis，SSc）是一种累及广泛结缔组织的自身免疫疾病，可导致皮肤及内脏器官纤维化和血管闭塞，预后差，死亡率高。至今尚无满意的防治方法。SSc早期病变主要是内皮和单核细胞参与的炎症过程，晚期是成纤维细胞主导的纤维化过程。文献报道CD146通过招募炎症细胞浸润参与多种自身免疫性疾病；我们前期研究发现CD146在SSc皮肤组织表达明显升高，基因敲除CD146明显改善博来霉素诱导的皮肤纤维化。因此，我们推测CD146可能是促进SSc进展的关键分子。本课题通过临床标本研究CD146与SSc病情的相关性；利用基因敲除小鼠和治疗模型，研究CD146抗体干预对炎症及纤维化进展的影响及其在调控细胞迁移、炎症细胞募集及促纤维化基因表达的作用，明确CD146在其中的分子机制。本研究将提出CD146可能是治疗SSc的新靶点，对研发防治SSc新药有着重要意。

背景：系统性硬化症是一种累及广泛结缔组织的自身免疫疾病，可导致皮肤及内脏器官纤维化和血管闭塞，预后差，死亡率高。至今尚无满意的防治方法。文献报道CD146通过招募炎症细胞浸润参与多种自身免疫性疾病。..研究内容：①通过临床标本，研究CD146 与SSc 病情的相关性。②建立博来霉素诱导小鼠皮肤纤维化抗体治疗模型，明确抗CD146 特异性抗体的干预对炎症细胞浸润、成纤维细胞活化及皮肤纤维化进展的影响。③分析 CD146 在调控细胞迁移、活化、炎症细胞募集及促纤维化因子表达的作用，从细胞水平明确CD146 在其中的分子机制。④从TGF-β 和wnt/β-catenin 信号通路的起始，活化，到靶基因的转录及翻译水平阐述 CD146促进成纤维细活化与迁移。..重要结果及研究意义：①CD146 在正常皮肤组织低表达，在SSc 患者和BLM 诱导的小鼠皮肤纤维化模型皮肤病变部位上调表达，其中成纤维细胞上CD146 上调最为明显；②抗CD146 单克隆抗体AA98 预防性或者治疗性给药，均能减少病变皮肤厚度，胶原含量和成纤维细胞数量，减轻皮肤纤维化程度；③CD146 促进Wnt1 刺激的人皮肤成纤维细胞增殖，迁移和纤维化基因表达，当用抗体AA98 处理，这种促进成纤维细胞活化的功能被抑制；④CD146 是经典Wnt 蛋白功能性受体， AA98 可以阻断Wnt/β-catenin 活化；⑤CD146 亦参与SSc 的炎症过程：纤维化病变组织的血管内皮细胞上CD146表达明显增强，抗体靶向CD146 明显降低了病变早期炎症细胞浸润。因此，CD146 有望成为治疗 SSc 的新靶点。