IMAGING INTIMAL HYPERPLASIA, MYOCYTE HYPOXIA, NECROSIS

内膜增生、心肌细胞缺氧、坏死的影像学检查

• 批准号: 6184656
• 负责人: LYNNE L. JOHNSON
• 金额: $ 24.21万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6184656
• 关键词: atherosclerosis; blood vessel prosthesis; blood vessel transplantation; cell proliferation; clinical research; coronary artery; human subject; hyperplasia; miniature swine; myocardial ischemia /hypoxia; necrosis; radiotracer; restenosis; swine; vascular smooth muscle

DESCRIPTION (Adapted from Applicant's Abstract): The broad objective of this grant is to investigate single photon imaging agents that specifically target either coronary vascular neointimal hyperplasia or hypoxic or necrotic myocardial cells using animal models and experimental designs relevant to clinical situations. Arteriosclerosis of the coronary arteries is a major health problem in the US and a leading cause of death. Catheter techniques to reduce luminal narrowing include percutaneous balloon angioplasty and coronary stenting. The pathology of restenosis following intracoronary stenting is neointimal proliferation comprised largely of smooth muscle cells. The mouse/human chimeric Z2D3 F(ab1)2 negative charge modified antibody radiolabeled with indium-111 Z2D3 targets a protein antigen on the surface of actively proliferating smooth muscle cells. In preliminary experiments, the applicants reported documenting in vivo uptake of In-111 Z2D3 in a swine model of stent overexpansion restenosis, but there was no correlation between the extent of neointimal proliferation or lumenal narrowing with intensity of tracer uptake. The applicants proposed therefore to look at the effect of another variable, the rate of smooth muscle cell proliferation on tracer uptake. Another disease process that compromises the coronary lumen due to neointimal proliferation is transplant arteriosclerosis which is the primary cause of death in patients after heart transplantation. Uptake of In-111 Z2D3 will also be investigated in a swine model of transplant arteriosclerosis produced by transplanting a segment of a coronary artery from a domestic pig into the carotid artery of a Yucatan minipig. Finally, two tracers that target the consequences of coronary flow reduction, ischemia (BMS-194796) and necrosis (glucarate), will be investigated. Glucarate, a 6 carbon atom dicarboxylic acid sugar, is a small molecule that is cleared rapidly from the blood pool and shows potential for clinical use in acute ischemic syndromes. Further experiments are proposed to confirm preliminary results of a study from our lab suggesting that glucarate uptake may be a sensitive marker for very early and very mild myocyte necrosis occurring with pacing and underlying coronary stenosis. BMS-194796, a nitroheterocycle, is retained in hypoxic tissue. The applicants reported to have recently documented uptake on in vivo imaging in a swine model of demand ischemia and propose to investigate the window for tracer retention and scan positivity before and after brief coronary occlusion mimicking an acute ischemic syndrome.

描述(改编自申请者摘要)：的总体目标 这项拨款是为了研究单光子显像剂，特别是 靶向冠状动脉血管新生内膜增生或缺氧性或 坏死性心肌细胞的动物模型及实验设计 与临床情况相关。冠状动脉硬化症 是美国的一个主要健康问题，也是导致死亡的主要原因。导管 减少管腔狭窄的技术包括经皮球囊 血管成形术和冠状动脉支架植入术。术后再狭窄的病理学研究 冠状动脉内支架置入术是一种新的内膜增生性疾病，主要由 平滑的肌肉细胞。鼠/人嵌合Z2D3F(Ab1)2负电荷 以In-111 Z2D3为靶标的修饰抗体 活跃增殖的平滑肌细胞表面的抗原。在……里面 初步实验，申请者报告记录了体内摄取 In-111 Z2D3在猪支架过度扩张再狭窄模型中的作用 新生内膜增殖的程度和管腔面积之间没有相关性 随着示踪剂摄取强度的增加而变窄。申请者建议 因此，要看另一个变量的影响，光滑率 肌细胞增殖对示踪剂摄取的影响。另一种疾病过程 因新生内膜增殖而损害冠脉管腔的移植 动脉硬化是心脏术后患者死亡的主要原因 移植。还将研究In-111 Z2D3在猪身上的摄取情况 移植物节段性动脉硬化模型的建立 从家猪到尤卡坦人颈动脉的冠状动脉 迷你猪。最后，针对冠状动脉血流后果的两种示踪剂 减少，缺血(BMS-194796)和坏死(葡萄糖酸盐)，将 调查过了。葡萄糖酸酯是一种6个碳原子的二羧酸糖，是一种 从血池中迅速清除并显示出的小分子 临床应用于急性脑缺血综合征的潜力。进一步的实验 建议确认我们实验室一项研究的初步结果 提示葡萄糖摄取可能是早期诊断的敏感指标。 在起搏和冠脉基础上发生非常轻微的心肌细胞坏死 狭窄。BMS-194796是一种硝基杂环，存在于缺氧组织中。 据报道，申请者最近记录了体内摄取情况。 在猪的需求缺血模型中进行成像，并建议研究 简要介绍前后示踪剂保留和扫描阳性的窗口 冠脉闭塞表现为急性缺血综合征。

项目成果

Imaging experimental atherosclerotic lesions in ApoE knockout mice: enhanced targeting with Z2D3-anti-DTPA bispecific antibody and 99mTc-labeled negatively charged polymers.

ApoE 敲除小鼠的实验性动脉粥样硬化病变成像：使用 Z2D3-抗 DTPA 双特异性抗体和 99mTc 标记的带负电荷的聚合物增强靶向。

• 发表时间: 2006
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Khaw,Ban-An;Tekabe,Yared;Johnson,LynneL
• 通讯作者: Johnson,LynneL

Uptake of 111In-Z2D3 on SPECT imaging in a swine model of coronary stent restenosis correlated with cell proliferation.

在猪冠状动脉支架再狭窄模型中 SPECT 成像中 111In-Z2D3 的摄取与细胞增殖相关。

• 发表时间: 2004
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Johnson,LynneL;Schofield,LorraineM;Weber,DeenaK;Kolodgie,Frank;Virmani,Renu;Khaw,BanAn
• 通讯作者: Khaw,BanAn