MOLECULAR IMAGING OF INFLAMMATION IN ATHEROSCLEROSIS

动脉粥样硬化炎症的分子成像

• 批准号: 8357882
• 负责人: Jonathan R Lindner
• 金额: $ 5.82万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357882
• 关键词: Algorithms; Anti-Inflammatory Agents; Anti-inflammatory; Atherosclerosis; Award; Binding; Cardiovascular system; Cell Adhesion Molecules; Characteristics; Clinical; Contrast Media; Development; Diagnostic; Disease; Disease model; Early Diagnosis; Endothelial Cells; Exercise; Functional disorder; Funding; Grant; Heart failure; Histologic; Human; Image; Immune response; Immunotherapy; Inflammation; Inflammatory Response; Injury; Intervention; Knock-out; Lead; Lesion; Ligands; Low Density Lipoprotein Receptor; Macaca mulatta; Modeling; Mus; National Center for Research Resources; Obesity; P-Selectin; Patient Care; Patients; Peptides; Phenotype; Play; Primates; Principal Investigator; Process; Relative (related person); Research; Research Infrastructure; Resources; Risk; Role; Safety; Severities; Source; Staging; Technology; Testing; Therapeutic; Ultrasonography; United States National Institutes of Health; Vascular Cell Adhesion Molecule-1; base; cost; human disease; imaging probe; interest; molecular imaging; nonhuman primate; novel; oxidized low density lipoprotein; response; technique development

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The development of techniques for molecular imaging of disease will likely lead to improvements in patient care through early diagnosis and customized phenotype-based treatment. Much of the recent progress in molecular imaging has been technology refinement whereby novel targeted probes and imaging algorithms have been tested in various models of disease. For cardiovascular applications, there is has been particular interest on imaging immune responses that play a critical role in atherosclerosis, ischemic injury, and heart failure. In the initial funding period of this award, we demonstrated that the severity of inflammation in murine models of atherosclerosis could be assessed with contrast-enhanced ultrasound and contrast agents targeted to endothelial cell adhesion molecules (ECAMs). These studies provided important information on binding characteristics, sensitivity of targeting ligands for disease processes. In this competitive renewal we will evaluate the relative clinical utility of this approach. We will determine whether molecular imaging of ECAMs provides unique diagnostic information that could positively impact patient care by guiding therapeutic decisions. One aim is to determine whether CEU targeted to VCAM-1 or P-selectin can detect the earliest stages of atherosclerosis prior to significant lesion development. This capability may be of critical value for assessing risk at a very early stage when novel potent anti-inflammatory therapies would be most effective. Hence, a second aim is to determine whether interventions aimed at the inflammatory response (immunotherapy against oxidized LDL or exercise) are most effective when given at the earliest sign of disease detected by molecular imaging. Sequential imaging studies will be used to determine whether suppression of ECAM expression predicts therapeutic response to treatment. These studies will be performed in two models of disease. The first is a reproducible murine model of atherosclerosis, the LDL-receptor and ApoBec editing peptide knockout, which will provide high-throughput and histologic confirmation. The second will be a novel non-human primate (rhesus macaque) model of obesity, inflammation and atherosclerosis which more closely resembles human disease. This model will be useful for determining the safety and feasibility for imaging with probes that are easily adaptable for human use. These studies will provide information on pathophysiology and response to therapy that will be critical for determining how molecular imaging can play a role for early diagnosis and optimizing management in patients with atherosclerotic disease.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 疾病分子成像技术的发展可能会通过早期诊断和基于表型的定制治疗来改善患者护理。分子成像领域的最新进展主要体现在技术改进上，新型靶向探针和成像算法已在各种疾病模型中进行了测试。对于心血管应用，人们特别关注在动脉粥样硬化、缺血性损伤和心力衰竭中发挥关键作用的免疫反应成像。在该奖项的初始资助期间，我们证明了可以通过超声造影和针对内皮细胞粘附分子（ECAM）的造影剂来评估动脉粥样硬化小鼠模型中炎症的严重程度。这些研究 提供了有关结合特征、靶向配体对疾病过程的敏感性的重要信息。在这次竞争更新中，我们将评估这种方法的相对临床实用性。我们将确定 ECAM 的分子成像是否提供独特的诊断信息，可以通过指导治疗决策对患者护理产生积极影响。目的之一是确定针对 VCAM-1 或 P-选择素的 CEU 是否可以在显着病变发展之前检测到动脉粥样硬化的最早阶段。当新型有效的抗炎疗法出现时，这种能力对于在早期阶段评估风险可能具有至关重要的价值。 最有效。因此，第二个目标是确定针对炎症反应的干预措施（针对氧化低密度脂蛋白的免疫疗法或运动）在分子成像检测到的最早疾病迹象时进行干预是否最有效。序贯成像研究将用于确定 ECAM 表达的抑制是否可以预测治疗反应。这些研究 将在两种疾病模型中进行。第一个是可重复的动脉粥样硬化小鼠模型，LDL 受体和 ApoBec 编辑肽敲除，这将提供高通量和组织学确认。第二个将是一种新型的非人类灵长类动物（恒河猴）肥胖、炎症和动脉粥样硬化模型，它更类似于人类疾病。这个型号 将有助于确定使用易于人类使用的探针进行成像的安全性和可行性。这些研究将提供有关病理生理学和治疗反应的信息，这对于确定分子成像如何在动脉粥样硬化疾病患者的早期诊断和优化治疗中发挥作用至关重要。