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

该提案是助理教授Sina Tavakoli博士的K08职业发展奖申请 匹兹堡大学心胸放射学博士。候选人的职业目标是成为一名独立人士 心血管疾病分子成像领域的内科医生和科学家。指导团队由以下人员组成 Carolyn Anderson博士，博士，Flordeliza Villanueva，医学博士，Prem Soman，医学博士，博士，Patrick Pagano，博士， 他们有指导成功的内科科学家的既定历史。这项建议源于 应聘者先前在巨噬细胞激活到不同阶段时代谢分化的经验 偏振状态及其对血管壁炎症成像的意义。 炎症的分子成像已被广泛研究以识别“易损斑块”。其中 目前临床上最常用的方法有(18F-脱氧葡萄糖)18F-FDG PET 学习。然而，18F-FDG针对普遍存在的代谢过程的有限特异性，存在不确定性 关于它的生物学相关性，以及它的高心肌摄取一直是其常规临床应用的主要障碍。 在动脉粥样硬化方面。最近的体外研究表明，增加谷氨酰胺的利用对于 巨噬细胞极化成M2(消炎)，而不是M1(促炎)，状态和可能 允许区分消炎和促炎巨噬细胞。在这里，我们的中心假设 谷氨酰胺和葡萄糖摄取的联合体内成像可以表征免疫- 动脉粥样硬化中巨噬细胞代谢的异质性及其与斑块组织学指标的相关性 脆弱性。我们提出三个具体目标： 特异性目的1：鉴定斑块巨噬细胞的免疫代谢特征及其与 动脉粥样硬化小鼠模型的易损性指数。 特异性目的2：确定18F-FDG和18F-氟谷氨酰胺在体内的潜在特性 小鼠动脉粥样硬化中的管壁炎症和对新型抗炎干预的反应。 特异性目的3：确定18F-FGln和18F-FDGPET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特征。 拟议实验的最终目标是：a)解决18F-FDG和 通过测定体内巨噬细胞亚群的免疫代谢谱来摄取18F-FGln B)探讨活体18F-FGln和18F-FDG PET定量检测的可行性 在检测动脉粥样硬化斑块的代谢异质性和监测抗动脉粥样硬化药物反应中的作用 炎症干预。这项研究的发现可能导致改善斑块的特征、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 对于肿瘤学成像的研究用途，这种方法可以很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.