Targeting MMPS to Image Atherosclerosis

以 MMPS 为目标进行动脉粥样硬化成像

• 批准号: 6950782
• 负责人: JAGAT NARULA
• 金额: $ 35.07万
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6950782
• 关键词: atherosclerotic plaque; bioimaging /biomedical imaging; cardiovascular disorder diagnosis; carotid artery; clinical research; coronary artery; endarterectomy; enzyme activity; enzyme induction /repression; genetically modified animals; histopathology; human subject; indium; inflammation; laboratory mouse; laboratory rabbit; metalloendopeptidases; monocyte chemoattractant protein 1; noninvasive diagnosis; protease inhibitor; radionuclide imaging /scanning; swine; technetium

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与冠状动脉的急性血栓闭塞有关，很可能是由于动脉粥样硬化斑块的破裂造成的。动脉粥样硬化斑块的破裂不一定与严重的梗阻病变相关，斑块破裂的可能性更好地由组织学特征确定。易受攻击的斑块通常表现为较大的脂核和被单核细胞强烈渗透的薄纤维帽。炎症与动脉粥样硬化斑块中金属蛋白酶的表达和激活直接相关，并可能构成炎症与斑块易损性之间的因果联系。因此，放射性核素靶向MMP1的产生和活性可以无创地检测到易破裂的斑块。 在这项拟议的研究中，铟-111标记的宽基金属蛋白酶抑制物(MPI)将用于检测实验性诱导的动脉粥样硬化斑块中的基质金属蛋白酶。此外，~(99m)Tm标记的单核细胞趋化蛋白-I(MCP-1)将被用于靶向动脉粥样硬化斑块中的炎症负荷。MPI多肽对MMP1-3、7-9和-13具有广泛的抑制特异性，抑制系数高，放射性标记多肽选择性地决定了MMP1-3、7-9和-13的表达程度。另一方面，放射性标记的重组人MCP-1是一种9-15 kD的单体多肽，可与单核/巨噬细胞上的MCP-1受体特异性结合，这些细胞在重新聚集到斑块中时上调。实验模型将包括脂肪喂养的兔子，以及可能存在更高程度的单核细胞渗透或基质金属蛋白酶产生的转基因动物。此外，还将研究糖尿病猪的冠状动脉和颈动脉弥漫性动脉粥样硬化性疾病。最后，从实验研究中获得的数据将被转化为开发一种临床诊断工具(作为概念验证)，用于最近发生脑血管事故的患者。炎症的程度和斑块中基质金属蛋白酶的表达将通过组织病理学来确定。 (摘要结束)