Magnetic Resonance Imaging of Cardiomyocyte Apoptosis

描述(由申请人提供)： 心肌细胞凋亡与许多心脏疾病有关，包括缺血、再灌注损伤和心力衰竭。然而，尽管在心肌细胞凋亡的生化特征方面取得了重大进展，但这一过程的临床意义仍不完全清楚。因此，这项建议的目的是开发在心力衰竭和再灌注损伤等疾病中对在体心肌细胞凋亡进行成像的能力。高分辨率磁共振成像和一种新型的磁性纳米颗粒AnxCLIO-Cy5.5将被用来完成这一任务。AnxCLIO-Cy5.5的合成已从最初报道的设计进行了修改，以显著提高其生物活性。我们现在假设：1)AnxCLIO-Cy5.5将以与未经修饰的Annexin相似的效率与凋亡的心肌细胞结合。2)该探针的灵敏度足以检测活体心肌细胞的凋亡。3)衰竭心肌AnxCLIO-Cy5.5摄取程度与心肌细胞凋亡程度相关。4)再灌注损伤后探针的蓄积模式对预后有相当大的意义。AnxCLIO-Cy5.5的初步体外和体内研究显示了非常令人鼓舞的结果。我们现在计划通过使用合适的手术和转基因小鼠模型，进一步研究该探针在活体内检测心肌细胞凋亡的敏感性。探头在MR图像上的累积将与心功能和心肌收缩能力的电影MR图像相关联。尤其要注意AnxCLIO-Cy5.5在再灌注损伤后的跨壁蓄积程度及其对节段性收缩功能的影响。拟议的研究将作为综合研究和培训计划的一部分进行，以促进申请者向研究独立性的过渡。这项拟议的研究还有可能促进对心肌细胞凋亡的更好理解，并加速开发新的心肌保护策略。

DESCRIPTION (provided by applicant): Cardiomyocyte apoptosis has been implicated in numerous diseases involving the heart including ischemia, reperfusion injury and heart failure. However, despite significant advances in the biochemical characterization of cardiomyocyte apoptosis, the clinical significance of this process remains incompletely understood. The aim of this proposal is thus to develop the ability to image cardiomyocyte apoptosis in vivo in diseases such as heart failure and reperfusion injury. High-resolution magnetic resonance imaging and a novel magnetic nanoparticle, AnxCLIO-Cy5.5, will be used to accomplish this. The synthesis of AnxCLIO-Cy5.5 has been modified from its originally reported design to significantly improve its biological activity. We now hypothesize that 1) AnxCLIO-Cy5.5 will bind to apoptotic cardiomyocytes with an efficiency similar to that of unmodified Annexin. 2) The sensitivity of the probe will be adequate to detect cardiomyocyte apoptosis in vivo. 3) The degree of AnxCLIO-Cy5.5 uptake in failing myocardium will correlate with the severity of cardiomyocyte apoptosis. 4) The pattern of probe accumulation following reperfusion injury will be of considerable prognostic significance. Preliminary in vitro and in vivo studies with AnxCLIO-Cy5.5 have shown highly encouraging results. We now plan to further investigate the sensitivity of the probe for the detection of cardiomyocyte apoptosis, in vivo, through the use of appropriate surgical and transgenic mouse models. Probe accumulation on the MR images will be correlated with cine MR images of cardiac function and myocardial contractility. Particular attention will be paid to the transmural extent of AnxCLIO-Cy5.5 accumulation after reperfusion injury and the effect this has on segmental contractile function. The proposed research will be conducted as part of an integrated research and training program to facilitate the applicant's transition to research independence. The proposed research also has the potential to facilitate a greater understanding of cardiomyocyte apoptosis and accelerate the development of novel cardioprotective strategies.