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CURRENT RESEARCH INTERESTS
Protein oxidation and posttranslational modification, mass
spectrometry, inflammation, oxidative stress, von Willebrand factor,
red blood cell.
RESEARCH
DESCRIPTION
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 exploring the molecular mechanisms controlling the oxidative
modifications of the proteases and protease inhibitors involved in the
tissue reactions to inflammation. Furthermore, we are 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 the structure and regulation
of blood coagulation proteins. We are currently attempting to
understand how von Willebrand factor (vWF) structure and function are
regulated by changes in its redox state. These studies are in
collaboration with Dr. Jose Lopez' research group. The long-term goals
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 are currently beginning to
apply 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
cells.
SELECTED
PUBLICATIONS
Fu X, Kassim SY, Parks WC, Heinecke JW.
Hypochlorous
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
276:41279-41287, 2001
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
278:28403-28409, 2003
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.
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