Magnetic Resonance Imaging of Cardiomyocyte Apoptosis

心肌细胞凋亡的磁共振成像

• 批准号: 6903138
• 负责人: David E Sosnovik
• 金额: $ 13.15万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6903138
• 关键词: annexins; apoptosis; bioimaging /biomedical imaging; biotechnology; cardiac myocytes; cardiovascular imaging /visualization; dextrans; diagnosis design /evaluation; disease /disorder model; genetically modified animals; heart disorder diagnosis; iron oxide; laboratory mouse; laboratory rat; magnetic resonance imaging; molecular /cellular imaging; molecular probes; myocardial ischemia /hypoxia; myocardium disorder; nanotechnology; newborn animals; pharmacokinetics; prognosis; protein binding

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.

描述（由申请人提供）： 心肌细胞凋亡与许多涉及心脏的疾病有关，包括缺血，再灌注损伤和心力衰竭。 然而，尽管心肌细胞凋亡的生化表征取得了重大进展，但该过程的临床意义仍未完全理解。 因此，该提案的目的是发展在心力衰竭和再灌注损伤等疾病中体内心肌细胞凋亡的能力。 高分辨率的磁共振成像和一种新型的磁性纳米颗粒（AnxClio-Cy5.5）将用于实现这一目标。 AnxClio-Cy5.5的合成已从其最初报告的设计中进行了修改，以显着改善其生物学活性。 现在，我们假设1）AnxClio-Cy5.5将与凋亡心肌细胞结合，其效率类似于未修饰的膜联蛋白。 2）探针的敏感性足以在体内检测心肌细胞凋亡。 3）心肌失败的AnxClio-Cy5.5摄取程度将与心肌细胞凋亡的严重程度相关。 4）再灌注损伤后探针积累的模式将具有相当大的预后意义。 具有AnxClio-Cy5.5的体外和体内研究的初步研究表现出极大的令人鼓舞的结果。 现在，我们计划通过使用适当的手术和转基因小鼠模型来进一步研究探针对心肌细胞凋亡检测的敏感性。 MR图像上的探针积累将与心脏功能和心肌收缩性的Cine MR图像相关。 再灌注损伤后，将特别关注AnxClio-Cy5.5积累的跨言语范围以及对节段收缩功能的影响。 拟议的研究将作为综合研究和培训计划的一部分进行，以促进申请人向研究独立性的过渡。 拟议的研究还有可能进一步了解心肌细胞凋亡并加速新型心脏保护策略。