CAREER: A Chemical Technology to Define Target-Specific Bioreactivity: Integrating Research and Education at the Crossroads of Chemistry and Biology

Cornell University, Ithaca NY

Investigators

Abstract

The inner workings of cells require exquisite orchestration of an array of individual chemical events. The various "instruments" communicate with one another through numerous signals, molecules that convey information about the state of the cell. For the proper function of cells, the timing of signaling is everything. In order to understand what is going on inside live cells, researchers routinely apply the signaling molecules to cells and observe what happens. There are serious limitations to this approach because the entire cell is exposed to the signal and timing is largely lost as the compounds find their way inside. These effects can lead to unintended consequences that can be impossible to sort out. The proposal aims to overcome these limitations, and to gain control over the exact location and timing of release of specific signaling molecules. The investigator addresses this pressing need by developing a set of new chemical tools with which reactive signals can be selectively delivered to specific proteins in cells at a precise time. Such a research breakthrough will provide time-resolved information on the chemically directed signal-processing mechanisms of fundamental importance in biology. The research enables graduate students in the lab to acquire excellent grounding in technological development interfacing chemistry and biology. The integrated outreach goal is to highlight modern crosscutting chemical biology concepts and tools, specifically aimed at K-12 educators and students from underrepresented populations. With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Assistant Professor Yimon Aye from Cornell University to evaluate with spatiotemporal precision the fundamental protein/small-molecule signal interactions. The non-enzymatic post-translational protein modifications inducible by the bioactive signaling electrophiles, such as lipid-derived aldehydes, have emerged to play major roles in redox-linked cell signaling. Avoiding the conventional whole-cell treatment approaches, this proposal introduces a new chemistry-driven approach to interrogate these interactions by selective chemical perturbation of one target with one inducer at a precise time in an otherwise native/healthy cell. The most recent data from the PI's lab suggest that her new directed modification strategy enables quantitative assessment of target- and electrophile-specific temporal dynamics of individual non-enzyme-assisted protein modification events in living cells. The knowledge of physiologically relevant reactivity and specificity will enable the prediction of how a given reactive small-molecule signal may function within microenvironments of a target in cellular decision-making.