With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Jeremy Baskin from the Department of Chemistry and Chemical Biology at Cornell University to develop chemical probes to study biological signaling pathways vital to the health and well-being of members of society, that are mediated by the lipid phosphatidic acid. Lipids are water-repellant molecules that, in biological systems, can act as energy stores, major constituents of cellular membranes, and intracellular signaling molecules. In the latter capacity, signaling lipids such as phosphatidic acid function as second messengers that cause cells to change their metabolism, gene expression, and behavior in response to diverse extracellular stimuli. To elucidate how the locations within the cell where phosphatidic acid is produced relates to each different physiological outcome, it is critical to be able to visualize and perturb the production of this key signaling lipid. The proposed research describes chemical and biochemical tools to both report on and control phosphatidic acid synthesis, as well as their application to study an important signaling pathway thought to be under the control of this lipid. This research to gain a deeper understanding of the chemistry and biochemistry of lipids integrates with an educational plan that entails hands-on outreach activities on lipids and biomembranes targeted at underserved populations in middle and high school, to increase awareness of and interest in science in young women and underrepresented minority students.
The lipid second messenger phosphatidic acid can, depending on the context, stimulate protein kinases to cause cell growth and proliferation, polymerization of actin to promote cell migration, and vesicle budding to increase protein secretion. It remains a mystery how one lipid signal can cause such diverse physiological events. The main impediment to dissecting the varied functional consequences of phosphatidic acid is a lack of tools to visualize and modulate its production with spatiotemporal control. The research objectives of this proposal are to develop a chemical method to image intracellular sites of phosphatidic acid production within live cells, to develop a chemoenzymatic strategy to enable production of phosphatidic acid on demand at precise, subcellular locations within live cells, and to apply these tools to probe mechanistic questions about the role of phosphatidic acid at lysosomes in orchestrating cell growth pathways. This work will generate both new methodologies for studying lipid signaling and fundamental knowledge into how a single lipid signaling agent can direct precise cellular signaling outcomes.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
