Molecular PET-MRI of Factor XIII activity for the detection of intravascular thrombosis and differentiation of its role in myocardial wound healing

尽管心力衰竭研究取得了最新进展，但每年仍有超过30万人死于缺血性心肌病。在寻求新的治疗策略，在体内分子成像允许新的方法来确定其病理生理的细胞和分子机制。因此，因子XIII被鉴定为缺血后伤口愈合中的关键酶。参与这一过程的因子XIII的来源仍然未知，无论是来自血管内凝血的血浆还是在单核细胞和巨噬细胞中发现的细胞。首先，本研究的目的是构建一个18 F-标记的探针PET检测因子XIII活性使用小鼠颈动脉血栓形成模型。这也是临床上的兴趣，因为在颈动脉血栓形成模型中检测因子XIII活性将是一种新的工具，用于直接和灵敏的成像急性动脉thrombosis.In下一步的探针应用于小鼠模型的心肌梗死使用PET-MRI。在用氯膦酸盐脂质体消耗巨噬细胞之前和之后，因子XIII活性相关的摄取将与通过纳米颗粒MRI评估的梗塞组织的巨噬细胞浸润相关。因子XIII活性与活心肌组织中巨噬细胞浸润的相关性可以区分血浆因子XIII和细胞因子XIII在心肌伤口愈合中的作用。

Despite recent advances in heart failure research, more than 300 000 people die each year from ischemic cardiomyopathy. On the quest for new therapeutic strategies, in vivo molecular imaging allows for new approaches towards identifying the cellular and molecular mechanisms of its pathophysiology. Hereby, Factor XIII was identified as a key enzyme in post ischemic wound healing. The origin of factor XIII involved in this process is still unknown, either plasmatic from intravascular coagulation or cellular as it is found in monocytes and macrophages. First, this study aims on constructing a 18F-labelled probe for PET detection of factor XIII activity using a mouse carotid artery thrombosis model. This is also of clinical interest, since the detection of factor XIII activity in a carotid thrombosis model would be a novel tool for direct and sensitive imaging of acute arterial thrombosis.In a next step the probe is applied in a mouse model of myocardial infarction using PET-MRI. Factor XIII activity related uptake will be correlated with macrophage infiltration of the infarcted tissue assessed by nanoparticle MRI, before and after macrophage depletion with clodronate liposomes. The correlation of factor XIII activity with macrophage infiltration in live myocardial tissue could allow for a differentiation between the effects of plasmatic and cellular factor XIII in myocardial wound healing.