Molecular imaging of vascular pathology

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DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in molecular imaging research. The principal investigator has completed residency training in radiology at Massachusetts General Hospital, and is a board certified radiologist. The principal investigator will now expand his scientific skills in a unique multidisciplinary environment and research program. The program is designed to promote an understanding of and skills necessary to conduct molecular imaging research, in a project that is scientifically rewarding and clinically relevant. Professor Ralph Weissleder will be the primary mentor for the principal investigator's scientific development. Professor Weissleder is the Director of Center for Molecular Imaging Research at Massachusetts General Hospital. He is a recognized leader in molecular imaging research and has an outstanding training record. The principal investigator will be co-mentored by Professor Alan Fischman, a recognized expert in radiopharmaceuticals and nuclear/PET radiology, and by Professor Michael Moskowitz, a world-renowned expert in stroke. High-risk ("vulnerable") atherosclerotic plaques are characterized by intense inflammation and the production of proteolytic and oxidative enzymes. This research program will focus on the development of enzyme-sensing magnetic resonance imaging (MRI) contrast agents and their validation in in vitro and in vivo settings. The overall hypothesis is that in vivo MRI of enzyme activity (e.g. peroxidase) measured by these "smart" agents will directly identify biologically vulnerable (active inflammatory) atherosclerotic lesions, thereby dramatically improving MRI's capability to characterize atherosclerotic plaques. Specifically, we aim to 1) synthesize highly sensitive substrates for MPO detection by exploiting structural modifications; to 2) validate the most promising substrates in biological systems, and to 3) validate the optimal substrates in a well-established animal model of atherosclerosis and correlate with immunohistochemical and biochemical studies.