Macrophage elastase and its imaging in vascular inflammation and remodeling

巨噬细胞弹性蛋白酶及其在血管炎症和重塑中的成像

基本信息

批准号：
9000577
负责人：
MEHRAN M SADEGHI
金额：
$ 51.12万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9000577
关键词：
Abdominal Aortic Aneurysm Address Affinity Aneurysm Animal Model Animals Arterial Fatty Streak Atherosclerosis Binding Biodistribution Blood Vessels Caring Cell Proliferation Cell membrane Cell surface Cells Cessation of life Computer-Assisted Image Analysis Detection Development Diving Early Diagnosis Effectiveness Elastases Enzyme Precursors Extracellular Matrix Family Fluorescent Probes Gene Deletion Health Heart Aneurysm Human Image In Vitro Inflammation Inflammatory Intervention Kinetics Label Lead Link MME gene Macrophage Activation Matrix Metalloproteinases Monitor Morbidity - disease rate Mus Myocardial Infarction Non-Invasive Cancer Detection Nuclear Outcome Pathogenesis Pathology Patients Peptide Hydrolases Phenotype Play Process Production Radiolabeled Risk Role Rupture Ruptured Aneurysm Source Specificity Structure Testing Therapeutic Intervention Time Tracer Vascular Diseases Vascular remodeling X-Ray Computed Tomography acute coronary syndrome base cell motility fluorescence imaging high risk imaging modality improved in vivo inflammatory marker inhibitor/antagonist macrophage member microSPECT molecular imaging monocyte morphometry mortality mouse model non-invasive imaging novel novel therapeutic intervention novel therapeutics overexpression prevent radiotracer research study scaffold single photon emission computed tomography targeted imaging three dimensional structure uptake vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Vascular diseases remain major causes of morbidity and mortality in the world. The availability of noninvasive imaging modalities for detection of features such as vessel wall inflammation and remodeling that are involved in, and increase the risk of vascular complications can help reduce this morbidity and mortality. Major existing gaps in the traditional approach to vascular imaging may be addressed by molecular imaging aimed at detecting relevant targets in vivo. To this means, tracers with broad specificity for matrix metalloproteinases (MMPs) have been developed and used to detect vascular remodeling and inflammation in vivo. While promising as first line agents, the effectiveness of these broadly specific agents is limited by diverse and at times opposing effects of different members of the MMP family in the pathogenesis of vascular remodeling and inflammation. Macrophage elastase (MMP-12) plays a key role in the development of atherosclerosis and aneurysm. RXP470, a selective and potent inhibitor of MMP-12, inhibits atherosclerotic plaque development and promotes a stable plaque phenotype. Here, we hypothesize that vessel wall inflammation and remodeling in atherosclerosis and aneurysm can be detected by molecular imaging of activated MMP-12 in vivo. Our specific aims are to develop and validate novel MMP-12-targeted tracers for molecular imaging and to validate the active form of MMP-12 as a marker of macrophage activation and target for imaging of vascular inflammation and remodeling in aneurysm and atherosclerosis. Based on the structure of RXP470 we have developed and preliminarily tested novel fluorescent and radiolabeled probes for molecular imaging. Here, this portfolio of tracers will be expanded and optimized for molecular imaging. The effectiveness of activated MMP-12 as a marker of inflammatory and vascular cell activation and differentiation will be addressed. Finally, complementary murine models of aneurysm and atherosclerosis will be used to validate MMP-12-targeted imaging for detection of vessel wall inflammation and remodeling by fluorescent imaging ex vivo and SPECT imaging in vivo. If validated, MMP-12 targeted imaging may identify patients at risk for acute coronary syndromes and aneurysm rupture and help track the effect of novel therapeutic interventions in vascular diseases.

描述（由申请人提供）：血管疾病仍然是世界上发病和死亡率的主要原因。无创成像方式的可用性用于检测所涉及的血管壁炎症和重塑等特征，并增加血管并发症的风险可以帮助降低这种发病率和死亡率。传统的血管成像方法中的主要差距可以通过旨在检测体内相关靶标的分子成像来解决。为此，已经开发并用于检测体内的血管重塑和炎症，对基质金属蛋白酶（MMP）具有广泛特异性的示踪剂。尽管有望作为一线代理，但这些广泛特异性药物的有效性受到MMP家族不同成员在血管重塑和炎症发病机理中的不同影响的限制。巨噬细胞弹性酶（MMP-12）在动脉粥样硬化和动脉瘤的发展中起关键作用。 RXP470是MMP-12的选择性和有效抑制剂，可抑制动脉粥样硬化斑块的发育并促进稳定的斑块表型。在这里，我们假设可以通过体内活化的MMP-12分子成像检测血管壁炎症和动脉瘤中的血管壁炎症和重塑。我们的具体目的是开发和验证新型的MMP-12靶向示踪剂进行分子成像，并验证MMP-12的主动形式，作为巨噬细胞激活的标志物以及用于动脉瘤和动脉粥样硬化中血管炎症和重塑的靶标。基于RXP470的结构，我们开发并初步测试了用于分子成像的新型荧光和放射标记探针。在这里，将扩展这种示踪剂组合，并优化用于分子成像。活化的MMP-12作为炎症和血管细胞激活和分化的标志的有效性将得到解决。最后，将使用互补的动脉瘤和动脉粥样硬化的鼠模型来验证MMP-12靶向成像，以检测血管壁炎症并通过荧光成像在体内进行荧光成像和Spect Image in Vivo进行重塑。如果经过验证，MMP-12的目标成像可能会鉴定出患有急性冠状动脉综合征和动脉瘤破裂风险的患者，并有助于跟踪新型治疗干预措施在血管疾病中的影响。