Molecular Imaging of Inflammation in Atherosclerosis

描述（由申请人提供）：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。这些研究为疾病过程中靶向配体的结合特性、敏感性提供了重要信息。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，此时新的强效抗炎疗法将是最有效的。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头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。公共卫生相关性：在这项提议中，动脉粥样硬化分子介质的超声成像将用于确定是否可以用非侵入性技术检测疾病的最早阶段。总体目标是确定在非常早期阶段的分子成像是否可以用于选择在疾病过程的早期给予可能有效的新治疗。这些研究为分子影像学在动脉粥样硬化中的应用提供了基础，从而通过早期发现和优化管理来改善患者的护理。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: In this proposal, ultrasound imaging of the molecular mediators of atherosclerosis will be used to determine whether the earliest stages of disease can be detected with non-invasive techniques. The overall aim is to determine whether molecular imaging at a very early stage can be used to select for new treatments that may work when given early in the disease process. These studies should provide the basis for the application of molecular imaging in atherosclerosis to improve patient care through early detection and optimization of management.