Targeting MMPS to Image Atherosclerosis

以 MMPS 为目标进行动脉粥样硬化成像

• 批准号: 7269390
• 负责人: JAGAT NARULA
• 金额: $ 33.21万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-22 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7269390
• 关键词: Acute; Animal Cancer Model; Animals; Arterial Fatty Streak; Atherosclerosis; Binding; CCL2 gene; Carotid Arteries; Cells; Characteristics; Clinical; Coronary; Coronary Occlusions; Coronary artery; Coronary heart disease; Data; Detection; Diagnostic; Diffuse; Disruption; Event; Experimental Models; Family suidae; Hand; Histologic; Human; Image; Incidence; Indium; Indium-111; Infiltration; Inflammation; Inflammatory; Label; Lesion; Link; Lipids; Matrix Metalloproteinases; Metalloproteases; Monocyte Chemoattractant Proteins; Mononuclear; Nuclear; Oryctolagus cuniculus; Patients; Peptides; Peroxidase; Production; Radioisotopes; Radiolabeled; Recombinants; Rupture; Specificity; Stroke; Technetium 99m; Translating; abstracting; base; concept; diabetic; feeding; inhibitor/antagonist; macrophage; monocyte; monocyte chemoattractant protein 1 receptor; polypeptide; radiotracer; research study; tool

DESCRIPTION (provided by applicant): The incidence of acute coronary events is associated with acute thrombotic occlusion of the coronary artery and is likely to result from rupture of the atherosclerotic plaque. The disruption of atheromatous plaque is not necessarily associated with severely obstructive lesions, and the likelihood of plaque rupture is better determined by histologic characteristics. The vulnerable plaques usually demonstrate sizable lipid cores, and thin fibrous caps which are intensely infiltrated by mononuclear cells. Inflammation is directly related to metalloproteinase (MMP) expression and activation in the atherosclerotic plaques, and may constitute the causal link between inflammation and plaque vulnerability. Therefore, radionuclide targeting of MMP 1 production and activity may allow noninvasive detection of the plaques susceptible to rupture. In the proposed study, indium-1 1 1 -labeled broad-based inhibitor of metalloproteinases (MPI) will be used for the detection of MMP in experimentally-induced atherosclerotic plaques. In addition, technetium-99m- labeled monocyte chemoattractant protein-I (MCP-1) will be employed for targeting of inflammatory burden in atherosclerotic plaques. MPI peptide has broad inhibitory specificity for MMP 1-3, 7-9 and -13 with high inhibitory coefficients, and radiolabeled peptide selectively determines the extent of MMP expression. On the other hand, radiolabeled recombinant human MCP-1, a monomeric 9-1 5 kD polypeptide, specifically binds to MCP-1 receptors on monocytes/macrophages upregulated during recruitment of these cells to the plaque. Experimental models will include lipid-fed rabbits, and genetically altered animals likely to harbor higher degree of monocytic infiltration or MMP production. In addition, diffuse atherosclerotic disease of coronary and carotid arteries will be studied in diabetic swine. Finally, the data obtained from the experimental studies will be translated to develop a clinical diagnostic tool (as a proof of concept) in patients with recent cerebrovascular accidents. The extent of inflammation and MMP expression in the plaques will be ascertained histopathologically. (End of Abstract)

描述（由申请人提供）： 急性冠状动脉事件的发生率与冠状动脉的急性血栓性闭塞相关，并且可能由动脉粥样硬化斑块破裂引起。动脉粥样硬化斑块破裂不一定与严重阻塞性病变相关，斑块破裂的可能性更好地由组织学特征决定。易损斑块通常表现为相当大的脂质核心和薄的纤维帽，单核细胞强烈浸润。炎症与基质金属蛋白酶（MMP）的表达和活化直接相关，可能是炎症与斑块易损性之间的因果联系。因此，放射性核素靶向MMP 1的生产和活动，可以允许非侵入性检测的斑块容易破裂。 在所提出的研究中，铟-111标记的金属蛋白酶（MPI）的广谱抑制剂将用于检测实验诱导的动脉粥样硬化斑块中的MMP。此外，锝-99m标记的单核细胞趋化蛋白-I（MCP-1）将用于靶向动脉粥样硬化斑块中的炎症负荷。MPI肽对MMP 1-3、7-9和-13具有广泛的抑制特异性，具有高抑制系数，并且放射性标记的肽选择性地决定MMP表达的程度。另一方面，放射性标记的重组人MCP-1，一种单体9- 15 kD多肽，特异性结合单核细胞/巨噬细胞上的MCP-1受体，在这些细胞向斑块募集期间上调。实验模型将包括脂质喂养的兔子，以及可能具有更高程度的单核细胞浸润或MMP产生的遗传改变的动物。此外，将在糖尿病猪中研究冠状动脉和颈动脉的弥漫性动脉粥样硬化疾病。最后，将从实验研究中获得的数据转化为近期脑血管意外患者的临床诊断工具（作为概念验证）。将通过组织病理学确定斑块中的炎症程度和MMP表达。 (End摘要）

项目成果

Noninvasive monitoring the biology of atherosclerotic plaque development with radiolabeled annexin V and matrix metalloproteinase inhibitor in spontaneous atherosclerotic mice.

使用放射性标记的膜联蛋白 V 和基质金属蛋白酶抑制剂在自发性动脉粥样硬化小鼠中无创监测动脉粥样硬化斑块发展的生物学。

• DOI: 10.1007/s12350-010-9276-5
• 发表时间: 2010
• 期刊: Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology
• 作者: Tekabe,Yared;Li,Qing;Luma,Joane;Weisenberger,Drew;Sedlar,Marija;Harja,Evis;Narula,Jagat;Johnson,LynneL
• 通讯作者: Johnson,LynneL