C1q/TNF-related protein-3在银屑病代谢紊乱中的作用及机制研究

Epidemiological studies suggest that patients with psoriasis are not only burdened with its symptoms, but also have an increased prevalence of metabolic disorders, including metabolic syndrome(MS)and cardiovascular comorbidities. It is believed that MS has significantly risk effect on severity and manifestations of psoriasis, but the molecular linker between these two diseases is not clear. C1q-TNF-related protein-3(CTRP3), a very important type of C1q family adipokines which modulate metabolic and immune response, has anti-inflammatory and cardiovascular protection functions. We hypothesis that CTRP3 serves as a molecular linker among psoriasis, metabolic disorders and cardiovascular comorbidities based on our pre-investigations of abnormal decreased CTRP3 levels in psoriasis patients compared to normal controls. To elucidate the pathogenic functions of CTRP3 in psoriasis, we will study the melocular mechanism of CTRP3 expression and the metabolic-regulated functions in vitro and in vivo. We also will investigate the anti-inflammatory functions in the homeostasis of the micro-immuno-environment of psoriasis patients. Our research reveals the function of CTRP3 in psoriasis pathogenesis and opens a new area of adiopkines of psoriasis treatment strategies.

银屑病与代谢综合征(MS)相关且心血管事件多发，严重影响银屑病的病情和转归，但机制不清。C1q-TNF-related protein-3(CTRP3)是一种具有调控代谢、炎症抵抗和心血管保护作用的新因子。我们发现银屑病患者CTRP3水平显著低于正常人，且银屑病效应分子TNF-α可下调其表达，CTRP3又与患者瘦素、脂联素水平相关。因此我们提出CTRP3可能是银屑病与代谢综合征的重要联系分子，一方面通过影响代谢使银屑病患者易患MS；另一方面使T细胞等产生更多的炎症因子，加重银屑病病情，形成一个银屑病与MS互为因果的恶性循环。本课题拟在明确CTRP3与银屑病相关的基础上，在体外实验和动物实验中分别研究1. 银屑病炎症因子对CTRP3表达及MS发生的影响；2. CTRP3对银屑病炎症发生发展的影响。深入探讨银屑病患者CTRP3水平和功能低下的机制，阐明CTRP3在银屑病患者发生MS中的意义。

银屑病（psoriasis）是一种慢性、复发性、顽固性红斑鳞屑性皮肤病。世界范围内自然人群中发病率约2%，且呈上升趋势。该病顽固难治，反复发作，严重危害患者的身心健康，影响生活质量。近年来临床观察统计发现，银屑病与多种代谢紊乱事件密切相关，包括肥胖、高血压、高血糖、高血脂以及代谢综合征（Metabolic Syndrome，MS）等多种临床症状,且与银屑病严重程度有关，会进一步恶化银屑病病情。更值得注意的是，银屑病人累积了多种缺血性心脏病和心血管疾病的风险因素。然而目前为止，银屑病与代谢紊乱事件相关的内在生物学联系和分子机制依然不明，愈发增加了银屑病治疗和恢复的难度。因此，探究银屑病人群多发代谢紊乱的原因成为亟待解决的问题。C1q-TNF-related protein-3(CTRP3)分子是近年来新发现的一种CTRP家族类细胞因子。既往研究报道CTRP3分子参与调控机体代谢，具有炎症抵抗作用，对心血管事件的发生具有保护作用。我们预实验发现银屑病患者CTRP3水平显著下降，提示其参与银屑病发生发展。项目执行中，通过银屑病的病例对照统计分析发现，银屑病人血清CTRP3水平较正常人显著下降，与代谢风险性因素负相关，与代谢保护性因子正相关；在高PASI评分的银屑病患者组水平更低，在饮酒患者群较非饮酒患者水平下降；系统性治疗银屑病后可恢复血清CTRP3水平。银屑病患者高表达的炎症因子TNFa和IL-17A可显著抑制人原代前体脂肪细胞分化成熟，继而显著抑制其分泌CTRP3和瘦素、脂联素。PPARγ分子是TNFa和IL-17A调控CTRP3表达的关键信号分子。涂抹重组CTRP3蛋白分子可以缓解咪喹莫特银屑病小鼠的炎症表型，降低炎症程度，抑制中性粒细胞的浸润和角质形成细胞的增殖及活化，具有保护性功能。初步证实CTRP3为银屑病与代谢综合征及心血管疾病的的内在分子联系，阐明CTRP3在银屑病患者发生代谢综合征中的纽带意义。