Research Projects
Kawasaki Disease
Kawasaki disease is a vasculitis of unknown etiology affecting primarily young children of all races, although it is especially prevalent among those of Japanese descent. In the United States, Kawasaki disease is the leading cause of acquired heart disease among children. We are using SELDI-TOF mass spectrometry to study protein profiles of children with Kawasaki disease, with the primary goal of identifying biomarkers that will add a molecular diagnostic to the existing case definition. We also have some preliminary evidence that protein patterns may be predictive of the efficacy of treatment.
We are establishing a collaborative research program to study in parallel the genetics, proteomics, and immune response of Kawasaki disease. Combining all these tools will hopefully go beyond developing a molecular diagnostic by elucidating pathogenic causes, biochemical mechanisms, and immune response pathways.
Outside resources
Kawasaki
Disease at The American Heart Assocation
The Kawasaki Disease Foundation
AHA 2004 Scientific Statement on Kawasaki Disease
Recent Work
Oral Presentation: Yasnovsky, J., Carlson,
S.M., Whitin, J.C., Pageler, N., Najmi, A., Burns, J., Cohen, H.J., "Plasma
Protein Patterns in Kawasaki Disease." AHA 8th International Kawasaki
Disease Symposium, San Diego, Feb 18 2005.
Statistical Analysis of SELDI-TOF Mass Spectroscopy
SELDI-TOF-MS technology is very new and mathematical methods for analysis of the data remain challenge in the field. We are developing integrated statistical and mathematical tools to preprocess spectra for proteomic analysis and to identify patterns or association among the proteins. Our algorithms are largely concerned with incorporating noise estimation directly into spectral processing, biomarker discover, and pattern identification.
Our preprocessing software is available for download from the Software page. Current projects include noise-aware clustering to both identify "aliased" proteins that appear as more than one peak in the mass spectra and time-series analysis of protein patterns.
Outside resources
SELDI technology at Ciphergen
Recent work
Carlson, S.M., Najmi, A., Whitin, J.C., Cohen,
H.J., "Improving Feature Detection and Analysis in SELDI-TOF Mass
Spectra." PROTEOMICS,
2005. 5(11).
Simultaneous
Spectrum Analysis software
Biology of Acquired Respiratory Distress
Syndrome
ARDS occurs in children as a result of systemic inflammation, often related to chemotherapy and/or radiation in preparation for bone-marrow transplants. A treatment for ARDS has recently been developed by Joe DiCarlo at Stanford in which patients' blood undergoes hemofiltration over a size-exclusion membrane with molecular weight cutoff between 10 and 35 kDalton. This treatment is thought to affect the concentration and distribution of proteins and small molecules throughout the blood, lymph, and interstitial fluid.
We are investigating how this treatment affects the low molecular-weight proteins and peptides present in blood with the goal of identifying cytokines or other small proteins that may be involved in triggering and/or maintaining the hyperactive immune response.
Outside resources
Background
on ARDS
Hemofiltration
to treat ARDS
Sulfur K-edge X-ray Absorption Spectroscopy of Intact Biological Tissues
The chemical speciation of sulfur can be elucidated by K-edge absorption spectroscopy of X-rays. At the Stanford Synchrotron Radiation Laboratory at the Stanford Linear Accelerator Center, it is possible to determine the proportions of the various oxidized and reduced forms of sulfur in complex mixtures. We collaborate with investigators at Stanford and the University of Saskatchewan to dynamically measure changes in these sulfur species in intact biological tissues, including living mammalian cells.
Outside resources
Stanford Synchrotron Radiation Laboratory
Stanford Linear Accelerator Center
Extracellular Glutathione Peroxidase (GPx3) Biochemistry
GPx3 is one of four known members of the mammalian glutathione peroxidase family, and contains an enzymatically active selenocysteine residue in its primary structure. GPx3 transcripts are found at high levels in the proximal tubules of the kidney and at lower levels in intestine, liver and lung. The enzyme GPx3 is found predominantly in plasma, but is also present in other extracellular fluids. In vitro GPx3 has antioxidant activity, specifically gluathione peroxidase activity. GPx3 levels in plasma are elevated in some models of oxidative stress, such as exposure to hyperoxia and experimental inflammatory bowel disease. We have developed a knockout mouse with targeted inactivation of GPx3 and are investigating whether these animals demonstrate increased susceptibility to oxidative stress.
Recent work
Tham, D.M., Whitin, J.C., and Cohen, H.J., Increased
expression of extracellular glutathione peroxidase in mice with dextran
sodium sulfate-induced experimental colitis. Pediatr Res, 2002. 51(5):641-6.
Whitin, J.C., Bharmre, S., Tham, D.M., Cohen, H.J., "Extracellular glutathione peroxidase is secreted basolaterally by human renal proximal tubule cells." Am J Physiol Renal Physiol, 2002. 283(1):F20-8.
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