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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL081170-05
Application #
7806509
Study Section
Special Emphasis Panel (ZHL1-CSR-O (M1))
Program Officer
Carlson, Drew E
Project Start
2006-09-01
Project End
2011-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$133,110
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Ali, Muhammad; Pulli, Benjamin; Chen, John W (2014) Molecular imaging of macrophage enzyme activity in cardiac inflammation. Curr Cardiovasc Imaging Rep 7:9258
Niers, Johanna M; Chen, John W; Lewandrowski, Grant et al. (2012) Single reporter for targeted multimodal in vivo imaging. J Am Chem Soc 134:5149-56
Su, Henry S; Nahrendorf, Matthias; Panizzi, Peter et al. (2012) Vasculitis: molecular imaging by targeting the inflammatory enzyme myeloperoxidase. Radiology 262:181-90
Zhang, Wei; Fulci, Giulia; Buhrman, Jason S et al. (2012) Bevacizumab with angiostatin-armed oHSV increases antiangiogenesis and decreases bevacizumab-induced invasion in U87 glioma. Mol Ther 20:37-45
Niers, Johanna M; Chen, John W; Weissleder, Ralph et al. (2011) Enhanced in vivo imaging of metabolically biotinylated cell surface reporters. Anal Chem 83:994-9
Swirski, Filip K; Wildgruber, Moritz; Ueno, Takuya et al. (2010) Myeloperoxidase-rich Ly-6C+ myeloid cells infiltrate allografts and contribute to an imaging signature of organ rejection in mice. J Clin Invest 120:2627-34
Rodriguez, Elisenda; Nilges, Mark; Weissleder, Ralph et al. (2010) Activatable magnetic resonance imaging agents for myeloperoxidase sensing: mechanism of activation, stability, and toxicity. J Am Chem Soc 132:168-77
McCann, Corey M; Waterman, Peter; Figueiredo, Jose-Luiz et al. (2009) Combined magnetic resonance and fluorescence imaging of the living mouse brain reveals glioma response to chemotherapy. Neuroimage 45:360-9
Rajendran, Reshmi; Ronald, John A; Ye, Tao et al. (2009) Nuclear microscopy: a novel technique for quantitative imaging of gadolinium distribution within tissue sections. Microsc Microanal 15:338-44
Ronald, John A; Chen, John W; Chen, Yuanxin et al. (2009) Enzyme-sensitive magnetic resonance imaging targeting myeloperoxidase identifies active inflammation in experimental rabbit atherosclerotic plaques. Circulation 120:592-9

Showing the most recent 10 out of 13 publications