CURRENT RESEARCH INTERESTS
Oxidative stress in inflammatory and thrombotic diseases, storage lesions of red blood cells and platelets, mass spectrometry
Research in the Fu lab employs mass-spectrometry based techniques to develop analytical methods for the elucidation of molecular mechanisms related to inflammatory and thrombotic disease states. Specifically, we are interested in how the redox status affects the function of blood clotting proteins such as von Willebrand factor (VWF) and ADAMTS13. We use mass spectrometry to quantitatively measure small molecular weight thiols and disulfides, and cleavage of VWF in plasma from patients with diseases that include sickle cell disease (SCD), thrombotic thrombocytopenia (TTP), von Willebrand’s disease (VWD), and trauma patients.
Our research also focuses on storage lesions of blood components. We use targeted and untargeted metabolomics approaches to study storage lesions of red blood cells and platelets, with an emphasis on metabolic pathways including lipid oxidation/degradation and other metabolites that may be involved in storage lesion. The goal is to identify biomarkers that may indicate poor storage and contribute to the pathogenesis of transfusion-related diseases.
Fu X, Kao J, Bergt C, Kassim SY, Hug NP, d'Avignon A, Parks WC Mecham RP, Heinecke JW. Oxidative cross-linking of tryptophan to glycine restrains matrix metalloproteinase activity. Specific structural motifs control protein oxidation. J Biol. Chem 279:6209-6212, 2004
Wang Y, Rosen H, Madtes DK, Shao B, Martin TR, Heinecke JW, Fu X. Myeloperoxidase inactivates TIMP-1 by oxidizing its N-terminal cysteine residue. an oxidative mechanism for regulating proteolysis during inflammation. J Biol. Chem 282(44):31826-34, 2007
Fu X, Gharib SA, Green PS, Aitken ML, Fraxer DA, Park DR, Vaisar T, Heinecke JW. Spectral index for assessment of differential protein expression in shotgun proeomics. J Proteome Res 7(3) 845-854, 2008
Gharib SA, Green PS, Aitken ML, Frazer DA, Park DR, Vaisar T, Heinecke JW, Fu X. Mapping the lung proteome in cystic fibrosis. J. Proteome Res. 8(6):3020-8, 2009
Yuan W, Wang Y, Heinecke JW, Fu X. Hypochlorous acid converts the γ-glutamyl group of glutathione disulfide to 5-hydroxy-butyrolactam: a potential marker for neutrophil activation. J. Biol. Chem. 284(39):26908-17, 2009
Rosen H, Klebanoff SJ, Wang Y, Brot N, Heinecke JW, Fu X. Methionine oxidation contributes to bacterial killing by the myeloperoxidase system of neutrophils. PNAS. 106(44):18686-91, 2009
Chen J, Fu X, Wang Y, Ling M, McMullen B, Kulman J, Chung D, López JA. Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13. Blood. 115(3) 706-12, 2010
Fu X, Chen J, Gallagher R, Zheng Y, Chung DW, López JA. Shear stress-induced unfolding of von Willebrand factor accelerates oxidation of key methionine residues in the A1A2A3 region. Blood. 118(19) 5283-91, 2011
Wang Y, Chen J, Ling M, López JA, Chung DW, Fu X. Hypochlorous acid generated by neutrophils inactivates ADAMTS13: an oxidative mechanism for regulating ADAMTS13 activity during inflammation. J. Biol. Chem. 290:1422-1431, 2015
Zimring JC, Slichter S, Odem-Davis K, Felcyn JR, Kapp LM, Bell LN, Gunst PR, Corson J, Jones MK, Pellham E, Bailey SL, Fu X. Metabolites in Stored Platelets Associated with Platelet Recoveries and Survivals. Transfusion, in press, 2016