Targeting MMPS to Image Atherosclerosis

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，并且可能是由动脉粥样硬化斑块破裂引起的。粥样斑块的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。易损斑块通常表现出相当大的脂质核心和被单核细胞强烈浸润的薄纤维帽。炎症与动脉粥样硬化斑块中金属蛋白酶（MMP）的表达和激活直接相关，并且可能构成炎症与斑块脆弱性之间的因果关系。因此，放射性核素靶向 MMP 1 的产生和活性可能允许对易破裂的斑块进行无创检测。 在拟议的研究中，铟-1 1 1 标记的广泛金属蛋白酶抑制剂 (MPI) 将用于检测实验诱导的动脉粥样硬化斑块中的 MMP。此外，99m锝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，抑制系数高，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9-1 5 kD 多肽）特异性结合单核细胞/巨噬细胞上的MCP-1 受体，在这些细胞募集到斑块的过程中上调。实验模型将包括脂质喂养的兔子和可能具有更高程度的单核细胞浸润或 MMP 产生的基因改造动物。此外，还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，从实验研究中获得的数据将被转化为针对最近发生脑血管意外的患者开发临床诊断工具（作为概念证明）。斑块中的炎症程度和 MMP 表达将通过组织病理学来确定。 （摘要完）

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)