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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 疾病分子成像技术的发展将可能通过早期诊断和基于表型的定制治疗来改善患者护理。最近在分子成像方面的大部分进展是技术改进，其中新的靶向探针和成像算法已经在各种疾病模型中进行了测试。对于心血管应用，对在动脉粥样硬化、缺血性损伤和心力衰竭中起关键作用的免疫应答成像特别感兴趣。在该奖项的最初资助期间，我们证明了动脉粥样硬化小鼠模型中炎症的严重程度可以通过对比增强超声和针对内皮细胞粘附分子（ECAM）的造影剂进行评估。这些研究 提供了重要的信息结合特性，灵敏度的靶向配体的疾病过程。在这次竞争性更新中，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了独特的诊断信息，可以通过指导治疗决策对患者护理产生积极影响。一个目的是确定是否CEU针对VCAM-1或P-选择素可以检测动脉粥样硬化的最早阶段之前，显着的病变发展。这种能力对于在非常早期的阶段评估风险可能具有关键价值，此时新的有效抗炎疗法将被应用于临床。 最有效。因此，第二个目的是确定针对炎症反应的干预措施（针对氧化LDL的免疫治疗或运动）在分子成像检测到的最早疾病体征时是否最有效。序贯成像研究将用于确定ECAM表达的抑制是否预测对治疗的治疗反应。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，更接近于人类疾病。该模型 将有助于确定使用易于适应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，这些信息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管理中发挥作用至关重要。