Research

One of the most important questions in modern biology is how cells maintain their identity and what are the genomic and proteomic changes that drive the transition of cells from a healthy to a diseased state. Deregulation of  kinase mediated signaling networks, often a consequence of receptor mutation or aberrant expression, has been shown to play an important role in cancer progression and the onset of other diseases. Therefore, it is essential to understand how different kinases interact with their pathways to produce diverse cellular behavior such as growth, proliferation, migration and differentiation. While traditional biochemical techniques have allowed us to understand how different components of the cell behave individually, a systems-level approach is required to understand how these components interact with each other, and how they function in the context of biological complexity.

The goal of our lab is to understand the mechanisms of kinase-mediated signaling at a systems level. The approach we are taking involves the development and application of novel mass spectrometry- and microarray-based methodologies to quantitatively measure dynamic changes of large numbers of signaling proteins of interest. In combination with systematic perturbations of protein expression and function, these tools allow us to use a global approach to determine the connectivity of the kinase-mediated signaling networks and the dynamics of their signaling. In addditon, we draw on well-established high-throughput gene expresion profiling and phenotypic measurements to examine the relationships between signaling dynamics, gene expression, cellular phenotype and disease progression. We then use these quantitative data to develop computational models of cellular signaling and to explore correlations between protein activity and phenotype. Ultimately, we envision that these efforts will allow us to not only elucidate the topology of signaling networks, but to make informed predictions about the most beneficial intervention strategies to regulate a phenotype or ablate a disease.

Some subjects of interest in our lab are:

  1. MYCN and TRKB synergy in Neuroblastoma
  2. Differential signaling between cancer stem cells and primary cancer cells in the context of glioblastoma
  3. Proteomic and genomic determinants in receptor tyrosine kinase signaling and functional specificity
  4. Developing proteomics tools to meassure absolute kinase abundance and stoichimetry of phosphorylation in human samples