HGF协同EPCs干预糖尿病心肌损伤的机制研究及分子影像评价

The main pathological alterations of diabetic cardiomyopathy include the microcirculation injury and myocardial fibrosis. The endothelial progenitor cells（EPCs）are beneficial for angiogenesis after injury, however, there is a progressive decrease of EPCs levels in diabetic cardiomyopathy. Clinically, the long-term prognosis of diabetic cardiomyopathy is poor due to the management difficulties, so the early intervention and regenerative therapy are paid more attention and gradually regarded as research hotspots. Based on our research achievements and previous studies, we consider hypothetically that hepatocyte growth factor(HGF) infected EPCs may be potential to inhibit ischemic myocardial fibrosis and regenerate the cardiac myocytes, and improve myocardial angiogenesis. If the hypothesis is further validated, there would be a prospective clinical application in the intervention of diabetic myocardial injuries. However, the synergistical mechanisms of EPCs infected HGF are still not fully understood. More importantly, a non-invasive, repeatable and dynamic method or modality for monitoring therapy procedure and assessing the therapeutic efficacy in vivo is still lacking. Thus, the specific aim of our study was to investigate whether the multimodal molecular imaging could be utlized to trace the EPCs expression and survival status. With target-specific type I collagen (GKWHCTTKFPHHYCLY) manganese nanoprobe, we are hopeful for assessing the myocardial fibrosis severity. Combined with cardiac T1-mapping, perfusion imaging and functional analysis on MRI, we will explore a new strategy for clarifing the mechanism of the synergy, noninvasive and dynamic monitoring of the therapy processes in vivo and quantitatively assessing the treatment effects using multimodal molecular imaging techniques. Furthermore, our study may be potential to provide scientific evidences and establish methodological strategies for early intervention of diabetic cardiomyopathy.

糖尿病心肌病以微循环损伤和心肌纤维化为主要病理改变，然而研究发现患糖尿病后有助于微血管修复的血管内皮祖细胞（EPCs）却进行性减少。目前糖尿病心肌损伤临床干预困难，远期预后差。因此，糖尿病心肌损伤的早期干预和再生治疗逐渐受到重视。综合文献报道及前期研究基础，申请者提出肝细胞生长因子（HGF）感染EPCs联合移植可协同促进微血管生成、抑制心肌纤维化并诱导心肌细胞再生，在干预糖尿病心肌损伤方面有较好的临床应用前景。但是，目前其协同作用机制尚需进一步阐明，且治疗过程中尚缺乏活体、动态、无创的监测及疗效评价手段。本课题拟利用多模态分子成像技术监测细胞表达和存活状况，并针对心肌I型胶原构建锰（Mn）纳米靶向特异性探针评价心肌纤维化严重程度；结合磁共振T1-mapping成像、灌注成像及功能成像等MR技术进行对照分析；阐释相关协同作用机制并获得动态治疗监测和疗效评价新方法，为临床治疗决策提供科学依据。

糖尿病心肌病（DCM）预后差，临床干预困难，血中内皮祖细胞（EPCs）进行性减少，故对其心肌损伤的干预逐渐成为研究热点并引起高度重视。课题组利用HGF感染EPCs联合移植治疗，从而实现协同抑制心肌纤维化、促进微血管生成，延缓心肌损伤过程。在治疗过程中，课题组研发了MPI/MRI/FLI多模探针和小分子MnL对比剂，深入探索了分子探针及成像材料的生物安全性；并利用多模态分子示踪成像技术监测EPCs细胞的表达活性、表达量及表达持续时间；经过序列优化和参数调整，结合MRI功能成像、灌注成像及T1 mapping等量化评价心肌微血管及纤维化程度；阐释了EPCs/HGF相关协同作用机制并获得在体、无创、动态的治疗监测方法，为糖尿病心肌损伤的疗效评价提供科学依据；与此同时，课题组将相关MRI成像方法应用于DCM临床研究，获得了系列研究成果，实现了部分技术的临床转化。