Molecular Imaging of Protease Activation in Aneurysm

动脉瘤中蛋白酶激活的分子成像

• 批准号: 8439670
• 负责人: MEHRAN M SADEGHI
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439670
• 关键词: Abdominal Aortic Aneurysm; Address; Anatomy; Aneurysm; Angiotensin II; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Aorta; Aortic Aneurysm; Atherosclerosis; Biology; Caliber; Cardiovascular Diseases; Cells; Clinical Research; Clinical Trials; Complication; Detection; Development; Diagnosis; Disease; Dissection; Doxycycline; Health; Health Care Costs; Healthcare Systems; High Prevalence; Image; Inflammation; Inflammatory; Infusion procedures; Link; Malignant Neoplasms; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Metabolism; Methods; Modeling; Morbidity - disease rate; Mus; Non-Invasive Cancer Detection; Operative Surgical Procedures; Outcome; Pathogenesis; Patients; Peptide Hydrolases; Performance; Photons; Play; Positron-Emission Tomography; Predictive Value; Preventive; Public Health; Risk; Risk Assessment; Risk Management; Rupture; Ruptured Abdominal Aortic Aneurysm; Smoking History; Source; Specificity; Spontaneous Rupture; Symptoms; TNF gene; Therapeutic; Therapeutic Intervention; Tracer; Treatment Cost; Ultrasonography; Vascular Diseases; Vascular remodeling; Ventricular Remodeling; Veterans; X-Ray Computed Tomography; base; fluorodeoxyglucose; gene therapy; high risk; imaging modality; improved; in vivo; inflammatory marker; infliximab; macrophage; meetings; men; middle age; molecular imaging; monocyte; mortality; novel; novel therapeutic intervention; patient population; public health relevance; repaired; single photon emission computed tomography; tomography; tool; uptake

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.

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率和死亡率的主要原因。基质金属蛋白酶（MMP）在主动脉动脉瘤的发病机理及其主要并发症，破裂和解剖中起关键作用。炎性细胞是血管壁中MMP活性的主要来源。动脉瘤的并发症在大型或有症状的动脉瘤中更频繁地发生，作为预防措施，通常将其用于手术或血管内修复。但是，在较小的动脉瘤中发生了许多并发症，这些并发症不符合手术修复标准。开发用于检测血管壁蛋白水解活性和动脉瘤炎症的非侵入性成像方法可能有助于鉴定出病态并发症高风险的小动脉瘤的子集。从经典上讲，18fluordeoxyoxyglucose（18F-FDG）成像用于检测与炎症情况相关的增强的代谢，尽管它缺乏炎症的特异性，但18F-FDG Imaging仍在临床研究中进行临床研究，用于检测炎症，因此高风险型腹主动脉aNeurysm。我们假设可以通过MMP激活的分子成像检测到主动脉动脉瘤中血管壁炎症，并且靶向MMP蛋白水解活性优于靶向18F-FDG的靶向增强代谢，以检测血管壁炎症并预测Aneurysm中的血管壁炎症和预测结果。 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血管壁生物学和动脉瘤的结局。通过血管紧张素II输注，将在小鼠主动脉中诱导动脉瘤。靶向MMP的微光谱成像将进行组织形态分析，以在示踪剂摄取和血管壁炎症之间建立关联。通过遗传干预和单核细胞耗尽对示踪剂摄取的调节功能的影响。与18F-FDG相比，在注射两种示踪剂的动物中，将解决以MMP为目标的示踪剂的性能。最后，将一组具有动脉瘤的动物放置在抗蛋白质水解或抗炎治疗上，并经过反复进行的MMP靶向成像，以确定分子成像的性能，以检测在这种情况下容纳血管壁炎症，蛋白水解活性和结果。通过确定可能从早期浸润性治疗中受益的高风险患者，开发用于检测动脉瘤血管壁炎症的成像方式可能会对公共卫生产生重大影响。此外，这种方法可以应用于对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。