CURRENT RESEARCH INTERESTS
Protein oxidation and posttranslational modification, mass
spectrometry, inflammation, oxidative stress, von Willebrand factor,
red blood cell oxidation.
Research in Dr. Fu's lab focuses on the role of
oxidation and other posttranslational modifications in the
pathogenesis of inflammatory and thrombotic diseases by incorporating
the use of mass spectrometry, proteomics and analytical
biochemistry. Currently, there are three specific areas: on three areas:
Matrix metalloproteinases (MMPs) and tissue
inhibitor of metalloproteinases (TIMPs).
MMPs function in homeostatic and repair processes, but dysregulation
of MMP activity is implicated in a variety of diseases, including
cancer, fibroses and inflammation. Our previous work has demonstrated
that hypochlorous acid, a reactive oxygen species generated by
neutrophils, regulates MMP activity by oxidizing specific amino
residues in the prepeptide (activation) and catalytic domains
(inactivation). We are now looking for in vivo evidence that
oxidative pathways regulate protease activity during inflammation.
Blood coagulation proteins. A second major effort in our laboratory centers on
oxidative regulation of blood coagulation proteins. We are currently
attempting to understand the molecular mechanisms through which
neutrophil-derived oxidants regulate von Willebrand factor (vWF) and
its cleavage enzyme, ADAMTS13 function. These studies are in
collaboration with Dr. José López' research group. The long-term
goal is to explore the functional consequences of posttranslational
modifications (PTMs) in blood coagulation proteins.
Red blood cell (RBC) storage lesion. It has been reported that the generation of RBC
storage lesion is associated with oxidation of the cell during
storage, but very little is known about the molecular mechanism. We
use proteomic approaches to study posttranslational modifications of
specific proteins, including hemoglobin and membrane skeletal
proteins, in red blood cells. Our long-term goal is to understand the
role of specific modifications, including oxidation, phosphorylation
and glycosylation, on the viability of stored and diseased red blood
Fu X, Kassim SY, Parks WC, Heinecke JW.
acid oxigenates the cysteine switch domain of pro-matrilysin (MM-7): A
mechanism for matrix metalloproteinase activation and atherosclerotic
plaque rupture by myeloperoxidase. J Biol. Chem
Fu X, Kassim SY, Parks WC, Heinecke JW.
Hypochlorous acid generated by myeloperoxidase modifies adjacent
tryptophan and glycine residues in the catalytic domain of matrix
metalloproteinase-7 (matrilysin): an oxidative mechanism for
restraining proteolytic activity during inflammation. J Biol Chem
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.
Green PS, Aitken ML, Frazer DA, Park DR, Vaisar T, Heinecke JW, Fu X.
Mapping the lung proteome in cystic fibrosis. J. Proteome Res.
Yuan W, Wang Y, Heinecke JW, Fu
X. Hypochlorous acid converts the g-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
oxidation contributes to bacterial killing by the myeloperoxidase
system of neutrophils.
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. (Chen J and Fu X contributed
equally to this work)