Molecular Imaging of Protease Activation in Aneurysm

描述（由申请人提供）： 血管疾病，包括主动脉瘤，是美国发病率和死亡率的主要原因。基质金属蛋白酶（MMPs）在主动脉瘤及其主要并发症破裂和夹层的发病机制中起关键作用。炎症细胞是血管壁中MMP活性的主要来源。动脉瘤并发症多发生在大的或有症状的动脉瘤中，作为预防措施，通常会进行手术或腔内修复。然而，大量并发症发生在不符合手术修复标准的较小动脉瘤中。开发一种用于检测动脉瘤中血管壁蛋白水解活性和炎症的非侵入性成像方法可能有助于识别具有高并发症风险的小动脉瘤子集。传统上，18F氟脱氧葡萄糖（18F-FDG）成像用于检测与炎症相关的代谢增强，尽管其缺乏炎症特异性，但18F-FDG成像正在临床研究中用于检测炎症，因此是高风险的腹主动脉瘤。我们假设主动脉瘤血管壁炎症可以通过MMP活化的分子成像检测，并且靶向MMP蛋白水解活性上级靶向18 F-FDG增强代谢，用于检测血管壁炎症和预测动脉瘤的结局。我们的具体目标是建立和验证MMP靶向单光子发射断层扫描（SPECT）/计算机断层扫描（CT）成像用于检测小鼠动脉瘤血管壁炎症，比较其与18 F-FDG检测动脉瘤炎症的性能，并评价MMP靶向成像用于检测抗蛋白水解和抗炎治疗对血管壁生物学和动脉瘤结局的影响。通过血管紧张素II输注在小鼠主动脉中诱导动脉瘤。MMP靶向microSPECT成像后将进行组织形态学分析，以确定示踪剂摄取与血管壁炎症之间的相关性。通过遗传干预和单核细胞耗竭对示踪剂摄取的调节单核细胞功能的影响将得到解决。将在注射两种示踪剂的动物中讨论MMP靶向示踪剂与18F-FDG相比预测动脉瘤结局的性能。最后，将对一组患有动脉瘤的动物进行抗蛋白水解或抗炎治疗，并进行重复的MMP靶向成像，以建立分子成像的性能，用于检测血管壁炎症、蛋白水解活性和在这种条件下的结果。用于检测动脉瘤血管壁炎症的成像模式的开发可能通过识别可能受益于早期侵入性治疗的高风险患者而对公共卫生产生重大影响。此外，这种方法可以应用于其他血管疾病的风险评估和管理，这些血管疾病与动脉瘤一起是退伍军人死亡的主要原因。

DESCRIPTION (provided by applicant): Vascular diseases, including aortic aneurysm, are major causes of morbidity and mortality in the US. Matrix metalloproteinases (MMPs) play a key role in the pathogenesis of aortic aneurysm and its major complications, rupture and dissection. Inflammatory cells are a major source of MMP activity in the vessel wall. Complications of aneurysm occur more frequently in large or symptomatic aneurysms, which as a preventive measure, are usually referred for surgical or endovascular repair. However, a large number of complications occur in smaller aneurysms which do not meet the criteria for surgical repair. The development of a non-invasive imaging approach for detection of vessel wall proteolytic activity and inflammation in aneurysm may help identify the subset of small aneurysms at high risk for morbid complications. Classically, 18Ffluorodeoxyglucose (18F-FDG) imaging is used for detection of enhanced metabolism associated with inflammatory conditions, and despite its lack of specificity for inflammation, 18F-FDG imaging is under clinical investigation for detection of inflamed, thus high risk abdominal aortic aneurysm. We hypothesize that vessel wall inflammation in aortic aneurysm may be detected by molecular imaging of MMP activation, and targeting MMP proteolytic activity is superior to targeting enhanced metabolism by 18F-FDG for detection of vessel wall inflammation and predicting outcome in aneurysm. Our specific aims are to establish and validate MMP targeted single photon emission tomography (SPECT)/ computed tomography (CT) imaging for detection of vessel wall inflammation in murine aneurysm, compare its performance in comparison with 18F-FDG for detection of inflammation in aneurysm, and evaluate MMP-targeted imaging for detection of the effect of antiproteolytic and anti-inflammatory treatments on vessel wall biology and outcome in aneurysm. Aneurysm will be induced in the mouse aorta through angiotensin II infusion. MMP-targeted microSPECT imaging will be followed by histomorphometric analysis to establish an association between tracer uptake and vessel wall inflammation. The effect of modulating monocyte function through genetic intervention and monocyte depletion on tracer uptake will be addressed. The performance of an MMP-targeted tracer in comparison with 18F-FDG for prediction of outcome in aneurysm will be addressed in animals injected with both tracers. Finally, a group of animals with aneurysm will be placed on anti-proteolytic or anti-inflammatory treatment and undergo repeated MMP-targeted imaging to establish the performance of molecular imaging for detection of vessel wall inflammation, proteolytic activity and outcome under such conditions. The development of an imaging modality for detection of vessel wall inflammation in aneurysm may have a major impact on public health by identifying high risk patients who may benefit from early invasive treatment. Furthermore, this approach may be applied to risk assessment and management of other vascular diseases, which together with aneurysm,are leading causes of mortality amongst veterans.