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Garret A. FitzGerald, MD, FRS | Institute for Translational Medicine and Therapeutics | Perelman School of Medicine at the University of Pennsylvania
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Our laboratory has two areas of interest—prostanoid biology and the role of peripheral molecular clocks in cardiovascular biology, metabolism and aging. Perhaps the distinguishing feature of our groups is that we pursue interdisciplinary translational science with a focus on therapeutics. Thus, we work in different model systems – mammalian cells, worms, fish and mice – but also in humans. Ideally we develop quantitative approaches that can be projected from our experiments in the model systems to guide elucidation of drug action in humans. To this end, we have long utilized mass spectrometry, initially to target the arachidonate derived lipidome, but more latterly also the proteome.
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Education
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MB, BCh
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University College, Dublin
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1979
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MSc (Statistics)
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School of Hygiene, University of London
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1980
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MD (Pharmacology)
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University College, Dublin
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Research Summary
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Currently, we are interested in several aspects of prostanoid research. We utilize a remarkably broad array of mutant mice to elucidate the biology of the two COX enzymes and the prostanoid receptors. We are particularly interested in the comparative efficacy and safety of pharmacological inhibition of COXs versus the microsomal PGE synthase– 1. We are interested in the potentially countervailing actions of prostanoids on stem cell differentiation and in elucidating the broader cardiovascular biology of prostaglandins D2 and F2α . Finally, besides inhibitors of mPGES–1 we are interested in the translational therapeutics of various receptor antagonists, aspirin and fish oils.
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In the area of clock biology, we are probing the role of the clock in aging in mice and worms and using cell specific deletions of core clock components to look at how communication paradigms between discrete peripheral clocks influence cardiovascular biology and metabolism. Finally, we are taking systems approaches to investigate how perturbation of peripheral clocks result in central clock dependent phenotypes.
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Finally, we are involved in the interdisciplinary PENTACON consortium designed to integrate basic and clinical research in 5 systems – yeast, mammalian cells, fish, mice and humans ( both in detail and at scale) – with the objective of predicting NSAID efficacy and cardiovascular hazard in patients.
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Selected Key Publications
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Mazaleuskaya, L.L., Lawson, J.A., Li, X., Grant G., Ricciotti E. and FitzGerald G.A. A broad-spectrum lipidomics screen of anti-inflammatory drug combinations in human blood. JCI Insight 1(12): e87031, 2016.
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Tang S.Y., Pawelzik S.-C., Chen, L., Lawson, J., and FitzGerald, G.A. Cardiovascular Consequences of Prostanoid I Receptor Deletion in Microsomal Prostaglandin E Synthase-1 -Deficient Hyperlipidemic Mice. Circulation 134(4):328-38, 2016.
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Liang X., Bettinger K., Abernathy D., Bushman R., and FitzGerald G.A. Bidirectional interactions between indomethacin and the murine intestinal microbiota. Elife 2015; 10.7554/eLife.08973.
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Hui Y, Ricciotti E, Crichton I, Yu Z, Wang D, Stubbe J, Wang M, Puré E, FitzGerald GA. (2010)Targeted deletions of cyclooxygenase-2 and atherogenesis in mice. Circulation 121(24): 2654-2660.
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Wang D, Patel V, Gao E, Rong Z, Levin M, Yu Z, Ferrari V, Lu MM, Xu J, Zhang H, Hui Y, Lawson J,Yi Y, FitzGerald GA. (2009)Cardiomyocyte cyclooxygenase –2 influences cardiac rhythm and function. Proc Natl Acad Sci 106: 7548-7552.
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Song, W., Paschos, G., Fries, S., Reilly, M., Rokach, J., Chang, C.-T., Patel, P.,Lawson, J. and FitzGerald, G.A. (2009).Novel EPA derived F3 isoprostanes as biomarkers of lipid peroxidation. J. Biol. Chem. 284: 23636-23643.
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Yu Y, Lucitt M, Stubbe J, Cheng Y, Jensen BL, Hansen B, Smyth E, FitzGerald GA. (2009)Prostaglandin F²α elevates blood pressure and promotes atherogenesis. Proc Natl Acad Sci 106: 7985-7990.
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Wang M, Zukas AM, Hui Y, Ricciotti E, Pure E, FitzGerald GA. (2006)Deletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis. Proc Natl Acad Sci 103: 14507-14512.
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Cheng Y, Wang M, Yu Y, Lawson J, Funk C, FitzGerald GA. (2006)Cyclooxygenases, mPGES-1 and cardiovascular function. J Clin Invest 116: 1391-1399.
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Egan K, Smyth E, Fries S, Rader D, FitzGerald GA. (2004)Prostacyclin confers atheroprotection on female mice. Science 306: 1954-1957.
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Grosser T, Yusuff S, Cheskis E, Pack MA, FitzGerald GA. (2002)Developmental expression of functional cyclooxygenases in zebrafish. Proc Natl Acad Sci USA 99: 8418-8423.
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Cheng Y, Austin SC, Rocca B, Koller BH, Coffman TM, Lawson JA, FitzGerald GA. (2002)Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 296: 539-541.
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Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, Vyas SN, FitzGerald GA. (2001)Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 345: 1809-1817.
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Kress GJ, Liao F, Dimitry J, Cedeno MR, FitzGerald GA, Holtzman DM, Musiek ES Regulation of amyloid-β dynamics and pathology by the circadian clock. J Exp Med. 2018 Jan 30. pii: jem.20172347.
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Skarke C., Lahens N., Rhoades S., Bittinger K., Bailey A., Hoffmann C., Olson R.S., Chen L., Yang G., Price T., Moore J., Grant G.R., Bushman F.D., Weljie A.M., & FitzGerald G.A. Characterization of the Human Chronobiome. Nature Scientific Reports 7(1):17141, 2017.
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Yang G., Chen L, Grant G.R.,Paschos G.,Musiek E.S.,Song W-L.,Lee V.,McLoughlin S.C., Grosser T., Cotsarelis G., and FitzGerald G.A. Timed expression of Bmal1 influences postnatal aging and survival. Sci. Trans. Med. 8(324):324ra16 2016.
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Liang X., Bushman R and FitzGerald G.A. Rhythmicity of the intestinal microbiota is regulated by gender and the host circadian clock. PNAS 112(33):10479-84, 2015.
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Baggs JE, Price TS, DiTacchio L, Panda S, FitzGerald GA, Hogenesch JB (2009)Network features of the mammalian circadian clock. PLoS Biol 7(3): e52.
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Curtis A, Cheng Y, Kapoor S, Reilly D, Price TS, FitzGerald GA. (2007)Circadian variation in blood pressure and the vascular response to asynchronous stress. Proc Natl Acad Sci 104: 3450-3455.
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Rudic RD, McNamara P, Curtis AM, Boston RC, Panda S, Hogenesch JB, FitzGerald GA. (2004)BMAL1 and CLOCK, two essential components of the circadian clock are involved in glucose homeostasis. PLOS Biol 2: 1893-1899.
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McNamara P, Seo S-B, Rudic RD, Sehgal A, Chakravarti D, FitzGerald GA. (2001)Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: A humoral mechanism to reset a peripheral clock. Cell 105: 877-889.
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FitzGerald G.A. ImPRECISION: Limitations to Interpretation of a Large Randomized Clinical Trial. Circulation.135 (2):113-115, 2017.
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Grosser T, Ricciotti E, FitzGerald GA. The Cardiovascular Pharmacology of Nonsteroidal Anti-Inflammatory Drugs. Trends Pharmacol Sci. Jun 23. pii: S0165-6147(17)30116-5, 2017.
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Paschos G.K. and FitzGerald G.A. Circadian clocks and Metabolism: implications for microbiome and aging. Trends in Genetics pii: S0168-9525(17)30127-0, 2017.
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Cline AM and FitzGerald GA. (2012)What Great Creation. Sci Transl Med 4(154): 154cm10.
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Paschos G. and FitzGerald G.A. (2010).Circadian clocks and vascular function. Circ. Res. 106(5):833-41.
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Skarke C and FitzGerald GA. (2010)Training translators for smart drug discovery. Sci Transl Med 2(26): 26cm12.
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Lab Address
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Institute for Translational Medicine and Therapeutics
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3400 Civic Center Boulevard, Building 421
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10th Floor, Room 122
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Philadelphia, PA 19104-5158
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Lab Telephone: 215-898-0255
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Lab Fax: 215-573-9004
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