Molecular Imaging of Protease Activation in Aneurysm

描述（由申请人提供）： 包括主动脉瘤在内的血管疾病是美国发病和死亡的主要原因。基质金属蛋白酶（MMP）在主动脉瘤及其主要并发症、破裂和夹层的发病机制中发挥着关键作用。炎症细胞是血管壁中 MMP 活性的主要来源。动脉瘤的并发症更常见于大型或有症状的动脉瘤，作为预防措施，通常转诊进行手术或血管内修复。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高风险并发症的小动脉瘤子集。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 18F-FDG 成像缺乏炎症特异性，但 18F-FDG 成像正在进行临床研究，用于检测发炎的高风险腹主动脉瘤。我们假设主动脉瘤中的血管壁炎症可以通过 MMP 激活的分子成像来检测，并且针对 MMP 蛋白水解活性优于 18F-FDG 来针对增强的代谢来检测血管壁炎症和预测动脉瘤的结果。我们的具体目标是建立和验证用于检测小鼠动脉瘤血管壁炎症的 MMP 靶向单光子发射断层扫描 (SPECT)/计算机断层扫描 (CT) 成像，比较其与 18F-FDG 检测动脉瘤炎症的性能，并评估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的 MMP 靶向成像。通过输注血管紧张素 II 在小鼠主动脉中诱导动脉瘤。 MMP 靶向 microSPECT 成像之后将进行组织形态计量分析，以建立示踪剂摄取与血管壁炎症之间的关联。将讨论通过遗传干预和单核细胞耗竭来调节单核细胞功能对示踪剂摄取的影响。将在注射两种示踪剂的动物中讨论 MMP 靶向示踪剂与 18F-FDG 的性能比较，以预测动脉瘤的结果。最后，一组患有动脉瘤的动物将接受抗蛋白水解或抗炎治疗，并进行重复的 MMP 靶向成像，以建立分子成像在这种条件下检测血管壁炎症、蛋白水解活性和结果的性能。通过识别可能受益于早期侵入性治疗的高危患者，开发用于检测动脉瘤中血管壁炎症的成像方式可能对公共健康产生重大影响。此外，这种方法可应用于其他血管疾病的风险评估和管理，这些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.