“解密型”组织因子靶向性多肽在易损斑块早期诊断中的研究

动脉粥样硬化易损斑块突然破损是引发急性心脑血管事件的重要原因，组织因子（TF）的活化已被证实与斑块的进展密切相关。活化的TF由“静密型”转化为“解密型”，促进了易损斑块的形成，但现有技术无法辨别斑块局部TF类型，如何通过检测“解密型”TF来预警易损斑块是本项目拟解决的关键问题。我们前期研究发现凝血因子VII来源的EGF1多肽可主动靶向TF，为本项目探讨针对“解密型”TF的多肽奠定了基础。预实验中，我们以TF上aa248-259为配体结合表位设计了多个EGF1衍生多肽，同时建立了近似天然膜环境的TF磷脂纳米盘（TF-Nanodisc）。本项目下一步拟利用TF-Nanodisc来模拟TF的活化过程，筛选出针对“解密型”TF特异性构象的多肽，并偶联超顺磁性氧化铁构建出纳米探针，结合磁共振成像在动物体内外模型中检测斑块易损性，为动脉粥样硬化易损斑块的早期诊断提供新途径。

Sudden breakage of vulnerable atherosclerotic plaque is an important factor to cause acute cardiovascular and cerebrovascular events; the activation of tissue factor (TF) has been confirmed to be closely related to atherosclerotic plaque occurrence, development and thrombus formation.Types of activated TF transform from “encryption” to “decryption”, promoting the formation of vulnerable atherosclerotic plaque; however, existing detection technologies are still unable to distinguish the types of TF in local plaque. How to achieve the early warning of the vulnerable plaque through detecting “decrypted”TF is the key problem which this study intends to solve. In previous study, we confirmed the EGF1 polypeptide stemming from the coagulation factor VII could target to TF , which laid foundation of our study on the polypeptide targeting “decrypted”TF. In preliminary experiments, we designed multiple EGF1 derivative polypeptides by serving aa248-259 of TF as a ligand as well as the TF-nanodisc similar to the natural membrane. Therefore, in the next step of our study, we intend to utilize TF-nanodisc to simulate the activation process of TF, screening polypeptides of specific conformation targeting “decrypted”TF , conjugating superparamagnetic iron oxide to establish nanoparticle probes and detecting the vulnerability of atherosclerotic plaques in vivo and vitro through MRI, which provides new ways for early diagnosis of vulnerable atherosclerotic plaque.