A Molecular Imaging Approach to Immuno-Metabolic Characterization of Vessel Wall Macrophages

本提案是助理教授Sina Tavakoli博士的K 08职业发展奖申请 匹兹堡大学心胸放射学教授候选人的职业目标是成为一名独立的 心血管疾病分子成像领域的医生兼科学家。指导小组由以下人员组成 Drs. Carolyn安德森，博士，Flordeliza Villanueva，医学博士，Prem Soman，医学博士，博士和帕特里克帕加诺，博士， 他们有指导成功的医学科学家的历史。该提案源于 候选人之前在巨噬细胞活化后代谢分化方面的经验， 偏振状态及其对血管壁炎症成像的影响。 炎症的分子成像已被广泛研究以识别“易损斑块”。之间 在各种方法中，（18 F-氟-脱氧葡萄糖）18 F-FDG PET最常用于临床 问题研究然而，18F-FDG靶向普遍存在的代谢过程的有限特异性， 关于其生物学相关性，以及其高心肌摄取一直是其常规临床应用的主要障碍 动脉粥样硬化。最近的体外研究表明，提高谷氨酰胺的利用是必需的， 巨噬细胞极化为M2（炎症消退），而不是M1（促炎），状态可能 允许区分炎症消退巨噬细胞和促炎巨噬细胞。在这里，我们的中心假设 谷氨酰胺和葡萄糖摄取的组合体内成像允许表征免疫- 动脉粥样硬化中巨噬细胞的代谢异质性及其与斑块组织学指标的相关性 易损性.我们提出三个具体目标： 具体目的1：确定斑块巨噬细胞的免疫代谢谱及其与 动脉粥样硬化小鼠模型的易损性指数。 具体目的2：确定体内18 F-FDG和18 F-氟谷氨酰胺在表征 血管壁炎症和对小鼠动脉粥样硬化中的新型抗炎干预的反应。 特定目的3：确定18F-FGln和18F-FDG PET在免疫组织学和代谢中的作用 人颈动脉内膜切除术标本的表征。 所提出的实验的最终目标是：A）解决18F-FDG的生物学相关性， 通过测定巨噬细胞亚群的体内免疫代谢谱来测定18F-FGln摄取。 斑块的微环境;和B）探索定量体内18 F-FGln和18 F-FDG PET的可行性 在检测动脉粥样硬化斑块的代谢异质性和监测抗- 炎性干预。这项研究的结果可能导致改善斑块特征，风险 对患者进行分层，并监测对新疗法的反应。考虑到18F-FGln的可用性 对于肿瘤学成像中的研究用途，该方法可以容易地转化为临床研究。

This proposal is a K08 Career Development Award application for Dr. Sina Tavakoli, an Assistant Professor of Cardiothoracic Radiology at University of Pittsburgh. The candidate’s career goal is to become an independent physician-scientist in the field of molecular imaging of cardiovascular diseases. The mentoring team consists of Drs. Carolyn Anderson, PhD, Flordeliza Villanueva, MD, Prem Soman, MD, PhD, and Patrick Pagano, PhD, who have an established history of mentoring successful physician-scientists. The proposal originates from the candidate’s previous experience in metabolic divergence of macrophages upon activation into different polarization states and its implications for imaging of vessel wall inflammation. Molecular imaging of inflammation has been extensively investigated to identify “vulnerable plaques”. Among the various approaches, (18F-fluoro-deoxyglucose) 18F-FDG PET has been most commonly utilized in clinical studies. However, the limited specificity of 18F-FDG, which targets a ubiquitous metabolic process, uncertainties about its biological correlates, and its high myocardial uptake have been major barriers to its routine clinical use in atherosclerosis. Recent ex vivo studies have shown that enhanced glutamine utilization is required for polarization of macrophages into M2 (inflammation-resolving), but not M1 (pro-inflammatory), state and may allow the distinction of inflammation-resolving from pro-inflammatory macrophages. Here, our central hypothesis is that combined in vivo imaging of glutamine and glucose uptake allows for the characterization of immuno- metabolic heterogeneity of macrophages in atherosclerosis and correlates with histological indices of plaque vulnerability. We propose three Specific Aims: SPECIFIC AIM 1: To identify immuno-metabolic profiles of plaque macrophages and their association with indices of vulnerability in a murine model of atherosclerosis. SPECIFIC AIM 2: To determine the potential of in vivo 18F-FDG and 18F-fluoroglutamine in characterizing vessel wall inflammation and response to a novel anti-inflammatory intervention in murine atherosclerosis. SPECIFIC AIM 3: To determine the role of 18F-FGln and 18F-FDG PET in immunohistological and metabolic characterization of human carotid endarterectomy specimens. The ultimate goals of the proposed experiments are: A) to address the biological relevance of 18F-FDG and 18F-FGln uptake by determining the in vivo immuno-metabolic profiles of macrophage subsets within the microenvironment of plaques; and B) to explore the feasibility of quantitative in vivo 18F-FGln and 18F-FDG PET in detection of metabolic heterogeneity of atherosclerotic plaques and monitoring the response to anti- inflammatory interventions. The findings of this study may lead to improved plaque characterization, risk stratification of patients, and monitoring the response to novel therapies. Considering the availability of 18F-FGln for investigational use in oncological imaging, this approach can be readily translated into clinical studies.