(I) Temporal analysis of signaling events using quantitative mass spectrometry based proteomics.

The general hypothesis for this project is that kinetics events which determine the order of S/T/Y phosphorylation in signaling proteins, also provide a temporal dimension to the activation or inhibition of downstream signaling pathways  (e.g. growth factor induced ordered phosphorylation of tyrosine residues in RTKs). Protein oxidation or mutations of critical amino acid residues in signaling proteins have an effect on the timing of phosphorylation events which can lead to “re-wiring” of signaling networks under oncogenic and/or oxidative stress conditions.

Ongoing projects developed under this hypothesis include:

Oxidative Stress and Growth Factor Signaling in Atherosclerosis. The major goals of this project are: (1) to identify the cysteine sites/signaling proteins susceptible to oxidation in response to PDGF or FGF stimulation under normal and oxidative stress conditions; (2) to monitor the effect of oxidation on the propagation of PDGF and FGF signaling pathways, and (3) in vivo investigation of the oxidation level of PDGFRbeta, FGFR1 and their downstream signaling proteins using the apoE KO mouse model for atherosclerosis.

Analysis of Redox Modulated Signaling Networks in Head and Neck Squamous Cell Carcinoma (HNSCC). Our long-term efforts are directed towards the identification of a subset of mutations critical for the onset of HNSCC, so that patient tailored therapies could be prescribed in the future. In collaboration with Dr. Mercedes Porosnicu, we are also involved in several Phase I/II clinical trials to define potential molecular predictors of response and resistance to combined radiation and targeted/chemotherapy in patients with HNSCC.

Redox and Phosphoproteomics Profiling of Signaling Networks in Response to Low-Dose Radiation. The long-term goal of these studies is the development of a high-throughput proteomics based classifier system for the analysis of radiation exposed tissue specimens. The classifier system could be used as a reporter to estimate the amount of radiation received by each individual (e.g. in the event of a terrorist attack when each victim will be exposed to a different amount of radiation depending on victim’s location relative to the radiation source).