树突状细胞在尿毒症加速性动脉粥样硬化中的作用及分子机制研究

Up until now, the pathogenesis of the atherosclerosis in uremic state are still unclear. Some researches suggest that uremic toxins is one of the main reasons.However, the dialysis patients who chronically use the dialysis tube, the dialyzers and other man-made materials distinctly have the phenomenon of immune activation. Besides the element of uremic toxins, we infer the immune activation plays a key role in the initiation of AS. In recent years, the effects of the inflammatory and immune responses in the initiation and progression of atherosclerosis were aroused growing concern. In recent years, the effects of the inflammatory and immune responses in the initiation and progression of atherosclerosis were aroused growing concern. The core of its theory is as following: under the antigen stimulation of the atherosclerosis and other risk factors, T-cells are activated which lead to a series of specific cellular and humoral immune response. Furthermore, effector cells are activated, such as the macrophages, the platelets, and the smooth muscle cells. This brings about the sudden increase of the inflammatory products. Later on, activation of these inflammatory cells may elicit plaque rupture resulting in acute cardiovascular events. Recent studies found the quantity and function of dendritic cells(DC) which is particularly important in the antigen presentation and the immune response regulation in vivo are changed in early period and late period of Atherosclerosis. Especially, DC may have close relationship with the quick development of Coronary heart disease in late period. Therefore, we intend to investigate the relationship and the possible signal transduction mechanism between the activation of DC in uremic patients and AS from vitro and in vivo. This will provide more therapeutic targers for the cardiovascular complications in uremic patients.

尿毒症状态下动脉粥样硬化（AS）的发病机制至今不明, 有研究提示毒素是其主要原因之一。但透析患者长期接触异物，明显存在免疫激活。故考虑除了毒素之外，免疫激活也是其导致AS的关键。近年来，炎症免疫反应在AS发生发展中的作用日益受到关注，其理论的核心是在抗原的刺激下，激活T淋巴细胞，引起的一系列特异性细胞免疫及体液免疫反应，进一步激活效应细胞，如巨噬细胞、血小板和平滑肌细胞，从而导致炎性产物的剧烈增加，促进AS发生发展。近年研究发现，具有抗原提呈和免疫应答调节的树突状细胞(DC)，在动脉粥样硬化的早期和晚期都有数量和功能的改变，尤其是DC可能与急剧进展有关。所以我们拟采用临床病例对照研究，利用流式细胞等技术对不同的尿毒症患者的外周血树突状细胞的分型和功能进行检测，并制备新型的高灵敏电化学免疫传感器从细胞水平上探讨DC与尿毒症AS的关系及其相关机制。为防治尿毒症心血管并发症提供更多的治疗靶点。

尿毒症状态下动脉粥样硬化的发病机制至今未明确，考虑有炎症及免疫两方面共同作用的结果。因我们研究组考虑DC与尿毒症加速动脉粥样硬化有密切观察，故我们通过构建ApoE-/-小鼠尿毒症加速性动脉粥样硬化模型，证实与普通动脉硬化比较，尿毒症加速性动脉粥样硬化小鼠的动脉内膜中成熟DCs增多，通过抑制动脉内膜及脾脏内DCs成熟，可以减轻动脉内膜粥样硬化病变，提示在防治尿毒症患者的慢性心血管疾病时，干预DCs将成为一个重要的靶点。并在人体试验中，通过构建基于目标物诱导双信号比率和聚合酶辅助的蛋白质循环放大构建的高灵敏的电化学核因子κB适配体传感器，使其在多个疾病标志物检测中得以应用。同时，因大量文献报道LncRNA在尿毒症发展中的重要作用，故我们进一步分析上传尿毒症相关基因数据，首次发现了lncRNA jhdm1d-as1与尿毒症的发展呈正相关，并在透析后进一步表达上调。为防治尿毒症加速动脉粥样硬化寻找新的生物标志物的靶位点提供新思路。并根据我们的研究成果发表5篇文章，其中SCi 4篇，并培养4名研究生，已有1名毕业。