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

血管壁巨噬细胞免疫代谢特征的分子成像方法

• 批准号: 10452574
• 负责人: Sina Tavakoli
• 金额: $ 16.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-17 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452574
• 关键词: 18F-Glutamine; Address; Anatomy; Angiography; Anti-Inflammatory Agents; Antibodies; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Autoradiography; Biological; Biological Assay; Cardiovascular Diseases; Carotid Endarterectomy; Catheters; Cell Culture Techniques; Cells; Cerebral Infarction; Clinical; Clinical Research; Complex; Decision Making; Detection; Development; Development Plans; Doctor of Philosophy; Endarterectomy; Endothelial Cells; Event; Glucose; Glutamine; Goals; Heterogeneity; Histologic; Human; Image; In Situ; Inflammation; Inflammatory; Interleukin-1 beta; Intervention; Investigation; K-Series Research Career Programs; Lead; Mentors; Metabolic; Metabolism; Mitochondria; Monitor; Mus; Myocardial; Myocardial Infarction; Myocardial perfusion; Patient Monitoring; Patients; Perfusion; Physicians; Physiological; Positron-Emission Tomography; Radiology Specialty; Recording of previous events; Research; Resolution; Role; Rupture; Scanning; Scientist; Smooth Muscle Myocytes; Soman; Spatial Distribution; Specificity; Specimen; Thrombosis; Tissues; Translating; Uncertainty; Universities; Vascular Diseases; Vascular Smooth Muscle; base; cancer imaging; cardiovascular risk factor; career; career development; clinical imaging; diagnostic strategy; embolic stroke; experience; experimental study; fluorodeoxyglucose; glucose uptake; high risk; imaging approach; improved; in vivo; in vivo imaging; indexing; macrophage; metabolic abnormality assessment; metabolic profile; molecular imaging; mouse model; non-invasive imaging; novel; novel diagnostics; novel therapeutics; professor; prospective; response; risk stratification; skills; treatment optimization; uptake

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.

该建议是助理教授Sina Tavakoli博士的K08职业发展奖申请 匹兹堡大学心胸放射学。候选人的职业目标是成为独立 心血管疾病分子成像领域的医师科学家。心理团队包括 博士。卡罗琳·安德森（Carolyn Anderson） 拥有精神上成功的身体科学家的悠久历史。该提议起源于 候选人以前在激活巨噬细胞代谢差异方面的经验 极化状态及其对血管壁炎症成像的影响。 已经对炎症的分子成像进行了广泛的研究，以鉴定“脆弱的斑块”。之中 各种方法（18F-Fluoro-deoxyglucose）18F-FDG PET最常用于临床 研究。但是，针对无处不在的代谢过程的18F-FDG的有限特异性，不确定性 关于其生物学相关性，其高心肌摄取是其常规临床使用的主要障碍 在动脉粥样硬化中。最近的离体研究表明，需要增强的谷氨酰胺利用率 将巨噬细胞极化为M2（解决炎症），而不是M1（促炎），状态和可能 允许与促炎性巨噬细胞区分炎症。在这里，我们的中心假设 是在谷氨酰胺和谷氨酰胺摄取的体内成像中结合的，可以表征免疫 - 动脉粥样硬化中巨噬细胞的代谢异质性，与斑块的组织学指数相关 脆弱性。我们提出了三个具体目标： 特定目的1：确定斑块巨噬细胞的免疫代谢谱及其与 在动脉粥样硬化的鼠模型中脆弱的指标。 特定目的2：确定体内18F-FDG和18F-氟谷氨酰胺在表征中的潜力 血管壁的炎症和对新型鼠动脉粥样硬化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。 拟议实验的最终目标是：a）解决18F-FDG和 通过确定巨噬细胞子集的体内免疫代谢特征，以18F-FGLN的吸收 斑块的微环境； b）探索定量在体内18F-FGLN和18F-FDG PET的可行性 在检测动脉粥样硬化斑块的代谢异质性时，并监测对抗抗菌的反应 炎症干预措施。这项研究的发现可能会改善牙菌斑的特征，风险 患者的分层，并监测对新疗法的反应。考虑18F-FGLN的可用性 为了在肿瘤成像中进行研究，可以将这种方法容易地转化为临床研究。