Integrated Chemical Proteomic Platforms to Probe Metabolic Signaling Across Scales of Space, Time and Reactivity

Biological systems are inherently heterogeneous, both at the molecular level (e.g., encoded proteins existing in distinct posttranslational modification states) and the cellular level (e.g., organization of biomolecules to distinct regions of a cell or distinct cells within a tissue). To understand regulatory mechanisms in these systems under normal or diseased states, we must be able to probe biomolecular function in native environments across scales of space and time. Existing proteomic platforms provide quantitative snapshots of the proteins present in a biological sample, yet these methods typically require homogenization of samples, signal-averaging over thousands-to-millions of cells, and provide no information on protein function. Therefore, innovation in the development chemical probes and technology platforms is needed to study protein activity within complex native environments. In the first part of this talk I will describe the development of new chemical probes and complimentary proteomic technologies to enable quantitative measurements in the proteome in native biological contexts—ranging from subcellular complexes, single cells, primary tissues to live animals. In the second half of this talk I will describe the integration of these platforms to discover new roles for reactive endogenous metabolites as intracellular signals in normal and diseased biological states, as well as the potential to regulate these signals for therapeutic benefit. Both halves of the talk will emphasize the role of these integrated chemical proteomic platforms as a discovery engine to identify novel targets for diagnostic and therapeutic development in human disease.