Research

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Research Interests

Our research interests focus on three main areas: 1) protein-protein interactions and their relation to disease 2) cell proliferation and differentiation 3) serum biomarkers for diagnosis and prognosis of cancer and psychiatric problems. We primarily use analytical biochemistry, protein chemistry and mass spectrometry. Current Research includes:

Investigation of the Tumor Differentiation Factor (TDF) system. TDF is produced by the pituitary gland and secreted into the blood stream, with identified putative receptor and no known mechanism of action. TDF and TDF-P1, a 20 amino acid peptide selected from the open reading frame of TDF, induce morphological and biochemical changes in vitro and in vivo that suggest that TDF is involved in differentiation of human breast and prostate cancer cells. Specifically, TDF induces markers of differentiation such as the polarization and formation of cell junctions and basement membrane, and furthermore induces milk protein synthesis and the over-expression of E-cadherin. However, TDF has no known morphological differentiation effect on fibroblasts or on kidney, hepatoma, and leukemic lymphocytic cell lines. The differentiation activity of TDF has not been reproduced by any of the known pituitary hormones or growth factors. TDF is secreted by the pituitary directly into the blood, suggesting an endocrine role. However, TDF protein is very under-studied. It is not yet clear where this protein acts and to what receptor it binds. In addition, the molecular mechanism through which TDF induces cell differentiation is not known. In our laboratory, we use TDF-P1 peptide to isolate and characterize potential TDF-receptor candidates.

In our recent study (Sokolowska et al., 2012), we used TDF-P1 peptide to isolate and characterize the potential TDF-receptor (TDF-R) candidates from MCF7 steroid-responsive breast cancer cells and non-breast HeLa cells. We further investigated the potential TDF-R in these two cell types and additionally in steroid resistant BT-549 cells (these cells do not express estrogen receptors) and HDF-a fibroblasts. Our results suggest that TDF-R candidates are members of the HSP70 protein family, are present on breast and cancerous cells, not other cells, and act through a novel steroid-independent pathway. The possibility that TDF-R is a multi-subunit, protein complex is also of interest. Currently we investigate the function of TDF and the mechanism through which this molecule induces cell differentiation. We also investigate the potential TDF-R candidates in DU145, PC3 & LNCaP prostate cancer cell lines, NG108 neuroblastoma and BLK CL.4 fibroblasts. We hypothetize that TDF induces differentiation of both breast and prostate cancer cells by binding through the same TDF-Rs and uses a common, parallel, steroid-independent pathway: the TDF pathway. See more in Sokolowska et al., (2012), J. Biol. Chem., 287(3):1719-33.

New Proteomic Approaches for breast and prostate cancer biomarker discovery. Another goal of our research is to identify serum biomarkers that detect and predict the progression of prostate and breast cancer. We use targeted proteomics; classical biochemical principles of protein fractionation, but in new, unexpected settings, that allow us to reveal and identify particular sub-proteomes.

In most of cases, cancer appears as a result of cell proliferation decoupling from cell differentiation. Therefore, monitoring both cell proliferation and differentiation within the same experiment could lead to superior results with higher confidence, compared with the current standard of care. Our predictions and preliminary data already point towards several proteins as potential biomarkers for cell proliferation and cell differentiation. We are trying to quantify these proteins by using mass spectrometry and to validate them as serum biomarkers for diagnosis of breast and prostate cancer and for prognosis of cancer aggressiveness. See more in Sokolowska et al., (2012), Electrophoresis (in Press) & Woods et al., (2012), Biochem. Biophys. Res. Commun., 419 (2): 305-8.

Proteomic analysis of sera and saliva from children with Autistic Spectrum Disorder (ASD) versus matched controls and correspondence with behavioral measures. Autistic spectrum disorders (ASD) are highly prevalent and increasing in incidence (1 in 88 children). ASD diagnosis often occurs only after symptoms are readily apparent. Extensive research has demonstrated that better behavioral outcomes occur when ASD treatment is initiated as early as possible. An easy method of detecting ASD in young, pre-verbal children would allow earlier and more effective treatment. Such detection could be accomplished using mass spectrometry and proteomic analysis of bodily fluids such as sera or saliva. Proteomics profiling of sera and saliva may help us understand the etiology of ASD. Therefore, we believe that detection of ASD in children through proteomics-based investigation of sera and saliva for identification of biomarkers would be a prime option. Our objective is to analyze the sera and saliva from children with ASD and age-matched normal controls using mass spectrometry and correlate any identified protein changes with social impairment measures (Social Skills Improvement System, SSIS). We also hypothesize that in the sera and saliva of children with ASD, cholesterol and associated carrier molecules are abnormal and that the magnitude of abnormality will correspond with ASD severity on social measures. This project is led by Dr. Alisa G. Woods, who bridges Biochemistry & Proteomics (our lab), Psychology (Dr. Jeanne Ryan, SUNY Plattsburgh), Biochemistry (Dr. Dudley, University of Swansea, United Kingdom), Psychiatry (Dr. Thome, University of Rostock, Germany) and Child Psychiatry (Drs. Taurines & Gerlach, University of Wuerzburg, Germany). See more in Woods et al., (2012), J.Cell.Mol.Med. (doi: 10.1111/j.1582-4934.2012.01543).

Analysis of transient protein-protein interactions in ephrin signaling. Ephrins and Eph receptors (EphRs) play an important role in nervous system and vascular system development. Disturbances in the ephrin system can lead to nervous system and vascular diseases. Understanding the signal transduction pathways activated by ephrin-EphR interactions is important for studies of both normal development and disease. Stimulation of EphRs leads to activation of signal transduction pathways and the formation of transient protein-protein interactions that trigger cytoskeletal remodeling. However, these protein-protein interactions are not well-studied. We study these intracellular events with a focus on characterizing protein-protein interactions and protein phosphorylation in the neuroblastoma-glyoma cell line as a model system. We have a special interest in investigating the function of a few specific proteins like WAVE1, WAVE2, Trk-fused gene and Nischarin in ephrin signaling. See more in Darie et al., (2011), Proteomics; 11(23): 4514-28.

 

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Potential P1 peptide (yellow) binding sites on model Hsp90 receptor protein (green). B and D: Closer view.