以ED-A(+)Fn为靶点超声纳米分子成像及靶向治疗心脏移植慢性排斥反应

项目名称： 以ED-A(+)Fn为靶点超声纳米分子成像及靶向治疗心脏移植慢性排斥反应

项目编号： No.81471677

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： 华兴

作者单位： 中国人民解放军第三军医大学

项目金额： 73万元

中文摘要： 心脏移植后慢性排斥反应（CR）所导致的移植物失活是目前心脏移植面临的最大难题。CR是一种以移植物弥漫性血管病变与心肌间质纤维化为主要病理特点的多因素疾病，其主要临床诊断手段包括血管内超声、血管造影、心肌心内膜活检等检查方法均具有明显的局限性，治疗上也无法达到早期、敏感及个性化，亟需一种能早期诊断并能以之为靶点和通路进行个性化治疗的新方法。ED-A+纤维连接蛋白胚胎剪接变体（ED-A+Fn）在CR移植心脏中特异性高表达且具有重要的功能性作用，还具有高亲和力的人重组抗体SIP-F8。结合前期研究基础，本课题拟制备携SIP-F8的纳米级超声微泡造影剂，以心肌内ED-A+Fn为靶点实现大鼠心脏移植CR超声分子成像，并以该微泡为载体携载ED-A+Fn-siRNA，靶向下调ED-A+Fn水平，评价其抑制CR的效果，为心脏移植后CR的早期诊断、动态监测与个性化治疗探索一种简便、安全的新方法。

中文关键词： 超声微泡；分子成像；基因治疗；靶向治疗；超声诊断

英文摘要： Chronic rejection (CR) post heart transplantation is the greatest obstacle that heart transplanation is facing presently. CR is a mutiple factor disease with the main pathologic characteristics of cardiac allograft vasculopathy and cardiac interstitial fibrosis. Its diagnostic modalities, including intravascular ultrasound, angiography and endomyocardial biopsy, all have obvious limitations, and its early therapy is difficult, being low in the sensitivity and the personalization, so there is an urgent need for a new method that combines early diagnosis and personalized therapy to a new target. ED-A+Fn is specifically expressed in the transplanted heart with CR and exerts important function in the development of CR, having a high affinity human recombinant antibody SIP-F8. Based on the previous researches, this study tries to prepare the nanoscale ultrasonic microbubbles carrying SIP-F8, realize the molecular imaging of CR targeting to ED-A+ Fn in myocardium in a rat heart transplantation model, introduce siRNA to down-regulate ED-A+ Fn expression with the microbubbles as the carrier and evaluate its effect on inhibiting CR, providing a new effective way for the early diagnosis, dynamic monitoring and personalized treatment of CR post heart transplantation.

英文关键词： nano-scale ultrasound microbubbles;Ultrasonic molecular imaging;targeted therapy;heart transplantation;chronic rejection