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.
Plaques characterization and prospective identification of vulnerable atherosclerotic plaques have remained a major clinical challenge. The proposed project explores the role of non-invasive imaging of glucose and glutamine uptake in characterizing vessel wall inflammation, a major driving factor of atherosclerotic plaque vulnerability. This approach may ultimately lead to the development of novel diagnostic approaches that help identify and optimize the treatment of patients who are at high risk of cardiovascular events, such as myocardial infarction and embolic stroke.