Research in the Fu lab focuses on disorders related to inflammation and thrombotic diseases, conditions that can be enhanced by our own immune systems. White blood cells respond to local sites of infection by releasing a host of factors capable of destroying invading pathogens and bacteria. One of the immune responses is to generate bacteria-killing oxidants which work just like bleach to “disinfect.” However, these powerful oxidants can also damage the surrounding healthy tissue, causing organ and/or blood vessel injury.
Our research uses mass spectrometry and biochemical methods to better understand the pathophysiology (abnormal functional changes) of a wide range of diseases related to inflammation and thrombosis and develop methods for prevention and new therapeutic strategies.
Areas of Study
Dr Fu’s Background
Research in our laboratory focuses on the role of protein oxidation and other post-translational modifications in the pathogenesis of inflammatory and thrombotic diseases by incorporating the use of mass spectrometry and analytical biochemistry. These studies encompass three primary areas:
Blood Coagulation Proteins
A major effort in our laboratory centers on the molecular mechanisms regulating blood coagulation proteins. We are currently investigating von Willebrand factor (VWF), ADAMTS13, and fibrinogen under oxidative conditions. We propose that oxidants produced by activation of inflammatory cells might modify the ability of ADAMTS13 to effectively cleave VWF. Furthermore, we are investigating the effects of fibrinogen oxidation and degradation products on its polymerization, which may play a key role in blood clotting events. These studies are in collaboration with Dr. José López at the Bloodworks Northwest Research Institute, as well as Investigators at the University of Washington. The long-term goal is to explore the functional consequences of post-translational modifications (PTMs) in blood coagulation proteins and to discover biomarkers for related diseases.
Red Blood Cell (RBC) Oxidation and Storage Lesion
It has been reported that the RBC storage lesion is associated with oxidation of the cell during storage, but very little is known about the molecular mechanisms. We are currently applying proteomic approaches to study the role of post-translational modifications to both membrane proteins and hemoglobin in the RBC storage lesion and RBCs from patients. 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.
Oxidative Stress Markers for Clinical Trials
Oxidative stress has increasingly been associated with the pathogenesis of a wide variety of diseases including sickle cell disease (SCD) and thrombotic thrombocytopenic purpura (TTP). In collaboration with Drs. Konkle and López, we are evaluating the use of N-acetylcysteine (NAC) as an antioxidant treatment in patients suffering from SCD or TTP, and are focused on determining relevant biomarkers for measuring oxidative stress. Glutathione (GSH) has long been identified as a biomarker of oxidative stress, but it is especially difficult to quantify in plasma and there are numerous related metabolites which may also be important in evaluating oxidative stress. We have developed a liquid chromatography-mass spectrometry (LC-MS) method to quantify a panel of small-molecule thiols and disulfides, including NAC, in a variety of sample types, representing the most complete LC-MS method to date. Our method can further be used to quantify the distribution of these thiols between free and disulfide form, including those bound to protein.
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