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

• 批准号: 8438063
• 负责人: MEHRAN M SADEGHI
• 金额: $ 51.77万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438063
• 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; Heart Aneurysm; Human; Image; In Vitro; Inflammation; Inflammatory; Intervention; Kinetics; Label; Lead; Link; MME gene; Macrophage Activation; Matrix Metalloproteinases; Modeling; 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; acute coronary syndrome; base; cell motility; high risk; imaging modality; improved; in vivo; inflammatory marker; inhibitor/antagonist; macrophage; matrix metalloproteinase 12; member; molecular imaging; monocyte; morphometry; mortality; novel; novel therapeutic intervention; prevent; public health relevance; radiotracer; research study; scaffold; single photon emission computed tomography; three dimensional structure; uptake; vascular inflammation

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率和死亡率的主要原因。无创成像模式的可用性，如血管壁炎症和重塑，参与和增加血管并发症的风险，可以帮助减少这种发病率和死亡率的检测功能。血管成像的传统方法中存在的主要差距可以通过旨在检测体内相关靶点的分子成像来解决。为此，已经开发了对基质金属蛋白酶（MMPs）具有广泛特异性的示踪剂，并用于检测体内血管重塑和炎症。虽然作为一线药物是有希望的，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制中的不同且有时相反作用的限制。巨噬细胞弹性蛋白酶（MMP-12）在动脉粥样硬化和动脉瘤的发生发展中起着关键作用。RXP 470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展并促进稳定的斑块表型。在此，我们假设动脉粥样硬化和动脉瘤中的血管壁炎症和重塑可以通过体内激活的MMP-12的分子成像来检测。我们的具体目标是开发和验证新的MMP-12靶向示踪剂的分子成像，并验证MMP-12的活性形式作为巨噬细胞活化的标志物和血管炎症和动脉瘤和动脉粥样硬化重塑的成像目标。基于RXP 470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性标记探针。在这里，这种示踪剂组合将被扩展和优化用于分子成像。活化的MMP-12作为炎症和血管细胞活化和分化的标志物的有效性将得到解决。 最后，将使用动脉瘤和动脉粥样硬化的互补鼠模型来验证MMP-12靶向成像，以通过离体荧光成像和体内SPECT成像检测血管壁炎症和重塑。如果得到验证，MMP-12靶向成像可以识别急性冠状动脉综合征和动脉瘤破裂风险的患者，并帮助跟踪血管疾病新型治疗干预措施的效果。