HSP90抑制剂通过PI3K/AKT信号通路调控SLE淋巴细胞增殖活化及治疗作用的研究

Systemic lupus erythematosus (SLE) is a very common autoimmune disease. Its mechanism is not completely clear, while the treatment is difficult. We previously found that HSP90 expression in SLE patients was increased, and then HSP90 may be a potential target for the treatment of SLE. Currently a variety of HSP90 inhibitors was used in research. Although only a few studies were about the treatment of.autoimmune diseases, the prospect is promising. There was a lack of in-depth study about the HSP90 as a target for the treatment of SLE. AKT is an important customer protein of HSP90. PI3K / AKT signaling pathway involved in mediating cell survival, growth and a variety of physiological processes, such as proliferation,differentiation, and are closely related to excessive activation of lymphocytes in SLE. We found HSP90 inhibitors reduced HSP90 expression can inhibit the activation of AKT. The issue with the above as a starting point, by MRL/lpr lupus mouse model, we try to study the effects of HSP90 inhibitors in the treatment of lupus, and meanwhile, respectively, the function and mechanism were researched. Such as to explore the effects on lymphocyte proliferation and cell cycle activation impacts and PI3K / AKT signaling pathway regulation by HSP90 inhibitors. This project not only aims to elaborate molecules involved in SLE pathogenesis of HSP90, also we try to provide a theoretical basis and foundation for therapy SLE with HSP90 inhibitors.

系统性红斑狼疮（SLE）是一种常见的自身免疫疾病，机制未完全明确，治疗困难。我们前期发现，HSP90在SLE患者体内特异性高表达，可能是潜在的治疗靶点。目前多种HSP90抑制剂已进入临床实验阶段，但在自身免疫性疾病中研究少，前景广阔，尚缺乏以HSP90为靶点治疗SLE的深入研究。AKT是HSP90的重要顾客蛋白，课题组前期还发现HSP90抑制剂可有效抑制AKT活化。PI3K/AKT信号通路参与细胞存活、增殖分化等多种生理过程，与SLE淋巴细胞过度活化密切相关。本课题以上述内容为切入点，从MRL/lpr狼疮鼠模型入手，研究HSP90抑制剂对其治疗作用，同时分别从功能研究和机制研究层面进一步探讨HSP90抑制剂对淋巴细胞增殖活化的影响以及淋巴细胞PI3K/AKT信号通路的调控。项目的实施旨在阐述HSP90分子参与SLE发病机理，也为HSP90抑制剂治疗SLE提供理论基础。

背景：系统性红斑狼疮是一种常见的自身免疫疾病，机制未明确，治疗困难，在HSP90在SLE患者 体内特异性高表达，可能是潜在的治疗靶点。目前多种HSP90抑制剂已进入临床实验阶段，但在自身免疫性疾病中研究少，前景广阔，尚缺乏以HSP90为靶点治疗SLE的深入研究。以MRL/lpr狼疮鼠为研 究对象，研究HSP90分子抑制剂（17-AAG)对其治疗作用，同时分别从功能研究和机制研层面进一步探讨HSP90抑制剂对淋巴细胞增殖活化的影响以及淋巴细胞PI3K/AKT信号通路的调控。主要研究内容：1、17-AAG对MRL/lpr狼疮鼠的治疗作用研究。2、17-AAG对MRL/lpr狼疮小鼠T淋巴细胞活化增殖研究。3、17-AAG对MRL/lpr狼疮鼠的治疗机制研究。重要结果：17-AAG干预MRL/lp r狼疮小鼠后,实验组尿蛋白减少，自身抗体ANA和ds-DNA水平下降，体重无明显差异。干预后的小鼠 的肾脏病理片提示炎症减少,免疫荧光强度变弱。关键数据：实验组、对照组体重（g）分别为：32.3 0±4.12、30.45±3.97;实验组对照组尿蛋白分别为（g/L）：8.71±3.87、21±2.47；实验组对照组ANA（pg/mL）分别为1047.35±237.54、1324.78±312.56；实验组对照组dsDNA（ng/mL） 分别为：23.11±3.14、31±4.25;实验组、对照组平均肾小球病变积分组分别为0.76±0.17、1.61 ±0.24，实验组较对照组浸润较轻。MTTT细胞增殖情况，各组在450nm在48h、72h、96h吸光值变化，ConA组：0.323±0.091、0.558±0.125、0.852±0.045；ConA+17-AAG0.5μM组：0 .213±0.081、0.480±0.127、0.791±0.123；ConA+17-AAG2μM组：0.159±0.002、0.18 6 ±0.005、0.261±0.004。科学意义:17-AAG有效降低狼疮鼠T淋巴细胞的异常增殖活化，可能通过有效抑制PI3K/AKT信号通路的异常活化，达到治疗SLE的作用。HSP90分子抑制剂17-AAG可明显缓解MRL/lpr狼疮鼠症状，对狼疮性肾炎起到保护作用。