Research Interests:

Bioactive lipids in inflammation and cardiovascular disease.

Keywords:

Prostaglandins, inflammation, atherosclerosis, oxidant stress, platelets, circadian, peripheral clock.

Research Summary:

The Pharmacology of COX Inhibition: A particular interest is to elucidate the cardiovascular biology of COXs and its implication for the use of aspirin, traditional NSAIDs and COX-2 inhibitors. Studies in mice and zebrafish complement studies of the genetic and environmental factors, which modulate response to this interesting class of compounds.

Eicosanoid Receptor Biology: Prostacyclin has potent vasodilator and platelet inhibitory properties. However, its role in vivo is poorly understood. Mice deficient in the prostacyclin receptor and mice overexpressing and lacking the thromboxane receptor are being employed to investigate this phenomenon. Current research also aims to investigate the molecular pharmacology of transporters, membrane and nuclear receptors activated by prostanoids, their interaction with proteins and integration into signaling pathways.

Isoeicosanoids : Isoeicosanoids are free radical catalyzed products of arachidonic acid with potential utility as indices of oxidant stress. Methods for analyzing representatives of distinct families of isomers continue to be developed, mass spectrometry. The mechanisms of formation of these compounds and their potential activities as incidental ligands at G protein coupled and nuclear receptors are being characterized. Alterations in isoeicosanoid generation are beging related to indices of oxidant injury to DNA and proteins and functional outcome in syndromes of oxidant injury in model systems and in humans.

Potential Lab Rotation Projects:

Eluciation of the role of Cox-2 in cardiovascular disease and cancer using tissue-specific deletion.

Proteomic and genomic analysis of inflammatory pathways in vascular cells.

Molecular mechanisms and metabolic and cardiovascular phenotypes of peripheral clocks.

Key References:

1. McNamara, P., Seo, S-B., Rudic, R. D., Sehgal, A., Chakravarti, D., and FitzGerald, G.A: Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: A humoral mechanism to reset a peripheral clock. Cell 105: 877-889, 2001.

2. Cheng, Y., Austin , S.C. , Rocca, B., Koller, B.H., Coffman, T.M., Lawson, J.A. and FitzGerald, G.A. Role of prostacyclin in the cardiovascular response to thromboxane A 2 . Science 296: 539-541, 2002. [ Commentary : Vane, J.R. Biomedicine. Back to an aspirin a day? Science 296: 474-475, 2002.]

3. FitzGerald, G.A. COX-2 and beyond: Approaches to prostaglandin inhibition in human disease. (Review) Nat. Rev. Drug Discov. 2: 879-890, 2003.

4. Bell-Parikh, C., Ide, T., Lawson, J.A., McNamara, P., Reilly, M. and FitzGerald, G.A. Biosynthesis of 15-deoxy- ) 12,14 -PGJ 2 and the ligation of PPAR ( . J. Clin. Invest. 112; 945 - 955, 2003. [Commentary. Powell W.S. 15-deoxy- ) 12,14 PGJ 2 - endogenous PPAR ( ligand or minor eicosanoid degradation product. J.Clin. Invest. 112; 828 - 830, 2003].

5. Rudic, R.D., McNamara, P., Curtis, A.M., Boston , R.C., Panda, S., Hogenesch, J.B. and FitzGerald, G.A. Circadian control of glucose homeostasis by Bmal1 and Clock. PLOS (in press), 2004.