靶向性调节性ODNR01减轻心肌缺血再灌注损伤及其机制研究

项目名称： 靶向性调节性ODNR01减轻心肌缺血再灌注损伤及其机制研究

项目编号： No.81470596

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 肖宏

作者单位： 华中科技大学

项目金额： 66万元

中文摘要： 最近的研究证实CD3+T淋巴细胞参与心肌缺血再灌注损伤（MIRI），Th1细胞分泌的IFN-γ和-γδ T/Th17细胞分泌的IL-17促进MIRI进程，其分化分别受到STAT1/4和STAT3通路调控。我们设计的调节性ODNR01通过干预STAT1/3/4磷酸化而抑制Th1和Th17细胞分化，但其对心肌组织STAT3磷酸化的抑制可能加重MIRI，即作用缺乏靶向性。本课题拟制备表面耦联CD3单抗并载带调节性ODNR01的免疫脂质体，即靶向性调节性ODN R01，观察其对CD3+T细胞的靶向性、Th1和Th17细胞分化和 γδT分泌IL-17的影响；应用靶向性调节性ODN R01干预MIRI小鼠，观察其对MIRI指标、T细胞亚群分化及炎症的影响，并通过体外实验阐明其机制。本课题的研究可望构建一种靶向CD3+ T细胞的调控MIRI炎症的化合物，为MIRI的免疫调节和靶向治疗奠定新的理论基础。

中文关键词： T细胞；缺血再灌注损伤；调节性ODN；炎症

英文摘要： Recent studies have suggested that CD3+ T lymphocytes played an important role in myocardial ischemia/reperfusion injury (MIRI). IFN- - γ secreted by Th1 and IL-17 secreted by γδ T/Th17, which are regulated by STAT1/4 and STAT3 pathway respectively, exacerbated MIRI. Regulatory ODNR01 designed by our group supressed differentiation of Th1 and Th17 through modulating phosphorylation of STAT1/3/4. However, suppressing STAT3 phosphorylation in myocardium could aggravated MIRI, which means this is not a targeting effect. The present research plans to 1) prepare targeted regulatory ODNR01 which is a kind of immunoliposome (IML) with CD3 antibody on its surface and regulatory ODNR01 inside, examine the CD3+ T cell targeting effect and influence on differentiation of Th1 and Th17, and secretion of IL-17 by γδT cell of this IML; 2) explore the effect of targeted regulatory ODNR01 on MIRI by evaluating MIRI index, T cell differentiation and inflammatory process and further clarify the detailed mechanism by in vitro experiments. Our study will construct a CD3+ T cell-targeting compound which could be used to regulate MIRI and provide the theoretical and experimental basis for the development of targeted therapy in MIRI.

英文关键词： T cell;ischemia reperfusion injury;regulatory ODN;inflammation