Development of mass spectrometry tools to study signaling networks in vivo. (360G-Wellcome-089028_Z_09_Z)

I propose to develop and refine state-of-the-art mass spectrometry-based phosphoproteomic tools to assess in vivo signaling networks. The first aim will be to develop a suite of mass spectrometry-based tools to understand how the microenvironment influences receptor tyrosine kinase (RTK)-mediated signaling and glioblastoma cellular responses in the context of a 3-dimensional (3D) extracellular matrix (ECM) in vitro model. In the second aim, I will extend and validate these in vitro mass spectr ometry approaches in an in vivo mouse xenograft system. Through the manipulation of RTK expression levels in glioblastoma xenografts, I will establish how RTK signaling networks regulate tumor responses in the brain. In collaboration with computational biologists (Dr Rune Linding, ICR), novel biological insights into the complex program by which the tumor microenvironment modulates intracellular signaling networks and biological responses will be gained by the implementation of phosphoproteomic data-driven computational models. Leads generated by these in silico approaches will ultimately be subjected to in vitro and in vivo experimental validation.