Department of Pharmacology & Chemical Biology at the University of Pittsburgh
Francisco J. Schopfer, PhD
Associate Professor
E1343 Thomas E. Starzl Biomedical Science Tower
200 Lothrop Street, Pittsburgh, PA 15213

Email:
fjs2@pitt.edu
Phone: 412-648-0193

Fax: 412-648-2229


Education

BS/MS (Biology), University of Buenos Aires, Argentina, 1998
PhD (Biochemistry), University of Buenos Aires, Argentina, 2001
MBA, University of Pittsburgh, 2011



Research Areas
Redox Pharmacology
Pharmacology of Cell and Organ Systems
Drug Discovery
Photo of Francisco J. Schopfer, PhD

Dr. Schopfer’s research is focused on the understanding of the biological effects of electrophilic fatty acids. In particular, he studies the mechanism by which nitrated fatty acid activate and signal through peroxisome proliferator-activated receptor gamma (PPARγ).  This receptor is the target of currently used antidiabetic drugs (thiazolidinediones). The activation of the receptor regulates fat and glucose metabolism, resulting in an overall decrease of glucose levels to normal values in patients with type II diabetes. The targeting of this receptor by nitrated fatty acids results in a decrease of the glucose levels to normal values like thiazolidinediones, but without the known secondary effects exerted by thiazolidinediones. In addition to the intrinsic therapeutic value of nitrated fatty acid, they will aid in the understanding of the biological mechanism involved in PPARγ activation, leading to improved designs of anti-diabetic drugs targeting the PPARγ receptor.

Figure 1

Fig 1. Modeling of PPARγ receptor activation by nitrated oleic acid

Biological effects of endogenous PPARϒ ligands

The role of the PPARγ receptor in diabetes has been well established. Nonetheless, the role of endogenous signaling molecules on the activation of PPARϒ is still unclear and under debate. Nitrated fatty acids are endogenously formed and bind to PPARγ with high affinity rivaling Rosiglitazone (thiazolidinediones), resulting in receptor activation. In addition, nitrated fatty acids covalently modify a critical cysteine (cys285) in the ligand binding pocket of PPARγ promoting a particular conformational change that results in partial receptor activation. This partial activation results in the expression of a particular subset of genes under PPARγ regulation and a biological outcome that differs from the one obtained when activating the receptor with Rosiglitazone. Dr. Schopfer’s work focuses on understanding the mechanism of this selective activation and how it avoids the side effect presented upon full activation by agonist like Rosiglitazone.
 
Endogenous formation of electrophiles and biological relevance
 
Electrophilic fatty acids are constantly formed as fatty acid breakdown products during oxidative stress and as signaling messengers by enzymatic or non enzymatic pathways. Dr. Schopfer studies the formation of biologically relevant electrophiles, in particular nitrated fatty acids, and their signaling mechanisms. The study involves the detection and characterization of novel electrophiles formed during inflammation. Once the molecules are characterized, a chemical synthesis approach is used to generate enough quantities for biological experiments.

Figure 2

Fig 2 A Key Reactivity of nitrated fatty acids: rapid, reversible Michael Addition reactions.

Proteomic analysis of electrophilic post-translational modifications

Electrophiles induce an important cellular response that includes the induction of phase II genes. This will in turn set up a more protective environment against damaging electrophilic molecules. A key player in the initiation of this biological response is the Keap 1/Nrf 2 couple. Keap 1 is usually bound to Nrf 2 in the cytoplasm. Upon formation of electrophiles, Keap 1, which contains several highly reactive cysteine, is targeted, dissociates from Nrf2 and is routed to degradation by the proteosome. These lead to Nrf2 nuclear translocation and activation of phase II genes. In particular, we study the mechanism by which different biologically relevant electrophiles target KEAP 1 and activate Nrf 2 responses. In addition, a more general proteomic approach is use to evaluate and characterize different electrophilic cellular protein targets. Once critical targets are identified using a mass spectrometry approach, a functional study of the modification is performed to determine the relevance and its cellular effects.





Important Publications
Bonacci G, EK Asciutto, SR Woodcock, SR Salvatore, BA Freeman and FJ Schopfer.  Gas-phase fragmentation analysis of nitro-fatty acids.  J Am Soc Mass Spectr 22:1534-1551, 2011.
Schopfer FJ, C Cipollina and BA Freeman.  Formation and signaling actions of electrophilic lipids.  Chem Rev 2011, in press.
Kansanen E, G Bonacci, FJ Schopfer, SM Kuosmanen, KI Tong, H Leinonen, SR Woodcock, M Yamamoto, C Carlberg, S Yla-Herttuala, BA Freeman and AL Levonen.  Electrophilic nitro-fatty acids activate NRF2 by a KEAP1 cysteine 151-independent mechanism.  J Biol Chem 286:14019-14027, 2011.
Bonacci G, FJ Schopfer, CI Batthyany, TK Rudolph, V Rudolph, NK Khoo, EE Kelley and BA Freeman.  Electrophilic fatty acids regulate matrix metalloproteinase activity and expression.  J Biol Chem 2011, in press.
Schopfer FJ, MP Cole, AL Groeger, CS Chen, NK Khoo, SR Woodcock, F Golin-Bisello, UN Motanya, Y Li, J. Zhang, MT Garcia-Barrio, TK Rudolph, V Rudolph, G Bonacci, PR Baker, HE Xu, C Batthyany, YE Chen, TM Hallis and BA Freeman.  Covalent peroxisome proliferator-activated receptor gamma adduction by nitro-fatty acids:  Selective ligand activity and anti-diabetic signaling actions.  J Biol Chem 285:12321-12333, 2010.
Groeger AL, C Cipollina, MP Cole, SR Woodcock, G Bonacci, TK Rudolph, V Rudolph, BA Freeman and FJ Schopfer.  Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids.  Nat Chem Biol 6:433-441, 2010.
Rudolph V, TK Rudolph, FJ Schopfer, G Bonacci, SR Woodcock, MP Cole, PR Baker, R Ramani and BA Freeman.  Endogenous generation and protective effects of nitro-fatty acids in a murine model of focal cardiac ischaemia and reperfusion.  Cardiovasc Res 85:155-166, 2010.
Zhang J, L Villacorta, L Chang, Z Fan, M Hamblin, T Zhu, CS Chen, MP Cole, FJ Schopfer, CX Deng, MT Garcia-Barrio, YH Feng, BA Freeman and YE Chen.  Nitro-oleic acid inhibits angiotension II-induced  hypertension.  Circ Res 107:540-548, 2010.




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