Gerald M. Rosen, Ph.D., J.D.
Isaac E. Emerson Professor
Dept. of Pharmaceutical Sciences
725 West Lombard Street
Baltimore, Maryland 21201, USA
- Lowell Technological Institute, Lowell, MA B.S. 1965 Chemistry
- Clarkson College of Technology, Potsdam, NY Ph.D. 1969 Organic Chemistry
- Duke University School of Law J.D. 1979 Law
The central theme of the grant to which Dr. Rosen is the PI, is the development of nitroxides as EPR imaging agents to quantify brain O2 levels and in particular, the distribution of O2 in the brain following stroke. For the past 38 years and 262 publications, Dr. Rosen has devoted his career to the synthesis of nitroxides, as probes to study physiologic function of biological systems. In the early 1980s, Dr. Rosen was one of the first scientists to synthesize nitroxides as MRI contrast media and conduct in vivo pharmacokinetic and MR imaging studies with these contrast agents. With the development of EPR imaging spectrometers, Dr. Rosen has established a long-term collaboration with Dr. Liu, the CoPI on this grant. Over the past few years, we have published a number of important papers on the development of blood-brain barrier permeable nitroxides specifically targeted to the brain to study physiology, thereof. In particular, the research proposed in this grant is a natural expansion of our joint collaborative research, which combines the unique expertise of Dr. Rosen in the design and synthesis of novel nitroxides and Dr. Liu in conducting EPR imaging and cerebral oxygenation during stroke.
1972 - 1978 - Assistant Professor of Pharmacology, Duke University.
1978 - 1985 - Associate Professor of Pharmacology, Duke University.
1985 - 1988 - Professor of Pharmacology, Duke University.
1988 - 1993 - Chair, Dept. of Pharmacology and Toxicology, University of Maryland School of Pharmacy
1990 - present - Isaac E. Emerson Professor, University of Maryland School of Pharmacy
Honors and Awards
Research Assistantship from NIH, 1965-1966; Teaching Assistantship, 1966-1969; Schering Fellow, 1967-1969; New York State Scholar, 1965-1969; Hoffmann-LaRoche Post-doctoral Fellow with Dr. Seymour Ehrenpreis, 1969-1970; NIH Research Post-doctoral Fellow with Dr. Seymour Ehrenpreis, 1970-1971; University Fellow with Dr. Peter Waser, University of Zurich, Switzerland, 1971-1972; NIH Young Investigator, Duke University, 1973-1975; NIH Career Development Awardee, Duke University Center for Aging and Human Development, 1977-1980; Andrew Mellon Science Policy Fellow at the National Academy of Sciences, 1980-1981; New York Academy of Sciences; Sigma Xi; Rho Chi; Isaac E. Emerson Professor of Pharmacology, University of Maryland, Baltimore, 1990; Eminent Scholar, the State of Maryland, 1999; The University System of Maryland Board of Regents Faculty Award for Excellence in Collaborative Research, 2009; Maryland section of The American Chemical Society, Chemist of the year for 2010.
Selected Peer-reviewed Publications - from a list of 262 publications
- G.M. Rosen, A. Beselman, P. Tsai, S. Pou, C. Mailer, K. Ichikawa, B.H. Robinson, R. Nielsen, H.J. Halpern and A.D. MacKerell, Jr. Influence of Conformation on the EPR Spectrum of 5,5-dimethyl-1-hydroperoxy-1-pyrrolidinyloxyl – A Spin Trapped Adduct of Superoxide. J. Org. Chem. 69: 1321-1330, 2004.
- J.P.Y. Kao and G.M. Rosen. Esterase-Assisted Accumulation of 3-Carboxy-2,2,5,5-tetramethyl-1-pyrrolidinloxyl into Lymphocytes. Org. Biomol. Chem. 2: 99-102, 2004.
- M.R. Dreher, M. Elas, K. Ichikawa, E.D. Barth, A. Chilkoti, G.M. Rosen, H.J. Halpern and M. Dewhirst. Nitroxide Conjugate of a Thermally Responsive Elastin-like Polypeptide for Non-invasive Thermometry. Med. Phys. 31: 2755-2762, 2004
- G.M. Rosen, S.R. Burks, M.J. Kohr and J.P.Y. Kao. Synthesis and Biological Testing of Aminoxyls Designed for Long-term Retention by Living Cells. Org. Biomol. Chem. 3: 645-648, 2005.
- J. Shen, S. Liu, M. Miyake, W. Liu, A. Pritchard, J.P.Y. Kao, G.M. Rosen, Y. Tong and K.J. Liu. Use of 3-Acetoxymethoxycarbonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl as an EPR Oximetry Probe: Potential for in vivo Measurement of Tissue Oxygenation in Mouse Brain. Magn. Reson. Med. 55: 1433-1440, 2006.
- M. Miyake, J. Shen, S. Liu, H. Shi, W. Liu, Z. Yuan, A. Pritchard, J.P.Y. Kao, K.J. Liu and G. M. Rosen. Acetoxymethoxycarbonyl Nitroxides as EPR Pro-Imaging Agents to Measure O2 levels in Mouse Brain: A Pharmacokinetic and Pharmacodynamic Study. J. Pharmacol. Exp. Therap. 318: 1187-1193, 2006.
- J.P.Y. Kao, E.D. Barth, S.R. Burks, P. Smithback, C. Mailer, K.-H. Ahn, H.J. Halpern and G.M. Rosen. Very-Low Frequency EPR Imaging of Nitroxide-loaded Cells. Magn. Reson. Med. 58: 850-854, 2007.
- C.S. Winalski, S. Shortkroff, E. Schneider, H. Yoshioka, R.V. Mulkern and G. M. Rosen. Targeted Dendrimer-based Contrast Agents for Articular Cartilage Assessment by MR Imaging. Osteoarthritis Cartilage, 16: 815-822 2008.
- P. Tsai, G.-L. Cao, T.J. Merkel and G.M. Rosen. Spin Labeling of Bacillus anthracis endospores: A Model for in vivo Tracking by EPR Imaging. Free Rad. Res. 42: 49-56, 2008.
- S.R. Burks, J. Ni, S. Muralidharan, A. Coop, J.P.Y. Kao and G.M. Rosen. Optimization of Labile Esters for Esterase-Assisted Accumulation of Nitroxides into Cells: A Model for In Vivo EPR Imaging. Bioconjug. Chem. 19: 2068-2071, 2008.
- C. Riplinger, J.P.Y. Kao, G.M. Rosen, V. Kasthirvelu, G.R. Eaton, S.S. Eaton, A. Kutateladze and F. Neese. Interaction of Radical Pairs Through-Bond and Through Space: Scope and Limitations of the Point-Dipole Approximation in Electron Paramagnetic Resonance Spectroscopy. J. Amer. Chem. Soc. 131: 10092-10106, 2009.
- J. Shen, R. Sood, J. Weaver, G.S. Timmins, A. Schnell, M. Miyake, J.P.Y. Kao, G.M. Rosen and K.J. Liu. Direct Visualization of Mouse Brain Oxygen Distribution by Electron Paramagnetic Resonance Imaging: Application to Focal Cerebral Ischemia. J. Cereb. Blood Flow Metabol. 29: 1695-1703, 2009.
- S.R. Burks, E.D. Barth, H.J. Halpern, G.M. Rosen and J.P.Y. Kao. Cellular Uptake of Electron Paramagnetic Resonance Imaging Probes through endocytosis of Liposomes. Biochim. Biophys. Acta, 1788: 2301-2308, 2009.
- S.R. Burks, L.F. Macedo, E.D. Barth, K.H. Tkaczuk, S.S. Martin, G.M. Rosen, H.J. Halpern, A.M. Brodie and J.P.Y. Kao. Anti-HER2 Immunoliposomes or Selective Delivery of Electron paramagnetic Resonance Imaging Probes to HER2-Overexpressing Breast Tumor Cells. Breast Cancer Res. Treat. 124: 121-131, 2010.
- M. Miyake, S.R. Burks, J. Weaver, P. Tsai, W. Liu, D. Bigio, K.S. Bauer, K.J. Liu, G.M. Rosen and J.P.Y. Kao. Comparison of Two Nitroxide Labile Esters for Delivering Electron Paramagnetic Resonance Probes into Mouse Brain. J. Pharm. Sci. 99: 3594-3600, 2010.
- S.R. Burks, M.A. Makowsky, Z.A. Yaffe, C. Hoggle, P. Tsai, S. Muralidharan, M.K. Bowman, J.P.Y. Kao and G.M. Rosen. The Effect of Structure on Nitroxide EPR Spectral Linewidth. J. Org. Chem. 75: 4737-4741, 2010.
- S.R. Burks, J. Bakhshai, M.A. Makowsky, S. Muralidharan, P. Tsai, G.M. Rosen and J.P.Y. Kao. 2H,15N-Substituted Nitroxides as Sensitive Probes for Electron Paramagnetic Resonance Imaging. J. Org. Chem. 75: 6463-6467, 2010.
For the past thirty-five years, my research has centered on the role of free radicals in biological systems. This research has focused on three goals: (a) the development of methods to detect and characterize free radicals generated during cellular activation in vitro and in vivo and (b) the investigation of the biological consequences of these reactive species and the synthesis of spin probes for magnetic resonance imaging (MRI) and electron paramagnetic resonance (EPR) imaging.
Central to the exploration of biologically generated free radicals is the ability to be able to identify and characterize these reactive species at the site of formation. The method of choice is spin trapping/electron paramagnetic resonance (EPR) spectroscopy, which has allowed the detection of free radicals, such as superoxide, hydroxyl radical and nitric oxide in animals in real time.
While production of free radicals, including superoxide and hydroxyl radical, has generally been associated with cytotoxicity, the recognition that nitric oxide controls a myriad of important physiologic activities, including host immune response, has ushered in a new era in free radical research. Of particular interest to my laboratory is the role of nitric oxide, generated by the immunological isozyme of nitric oxide synthase, in the control of blood-borne pathogens.
Research in the laboratory also focuses on the design and synthesis of dendrimer-linked nitroxides as magnetic resonance imaging (MRI) contrast agents for arthritis. In vivo MR imaging experiments have demonstrated that these compounds are selective contrast agents that specifically bind to joint cartilage. Research is ongoing to determine how early in the development of arthritis can these MRI contrast agents detect changes in cartilage status, becoming valuable diagnostic tools for early detection of arthritis.
Finally, to use MRI effectively to identify pathologies, such as tumors, probes are necessary to measure changes in the physiologic status of a tissue. Probes are also needed for EPR imaging that, unlike MRI, could be used to track and visualize cell movements in real time within the body, such as the spread of metastatic cancer cells or where stem cells localize after introduction into the body. These probes need to be both magnetic and highly specifiable to permit tagging and tracking of specific cell types or biologically active molecules. Depending upon the specificity of the probe, EPR imaging can even monitor changes in brain oxygen levels that can assist in therapeutic intervention after stroke or drugs of abuse.
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