This project will shed new light on the role of lipids in cell biology. Lipids form barriers that define cells and their internal compartments. They are also recently recognized for their critical roles as signaling molecules, regulating cellular processes. It is now clear that cells produce thousands of unique lipid species with diverse functions. However, the individual functions of these lipid species remain unclear. Within this context, this project applies state-of-the-art chemical biology and analytical approaches to investigate the role of specific lipids in different cell fates. By doing so, this study will reveal novel mechanisms underlying fundamental cellular processes. The comprehensive methodological tools employed in this project allows training a globally competitive workforce across the educational spectrum involving participation of underrepresented student groups and teachers in research and scientific inquiry.
This project will elucidate the function of lipids during cell death, providing a better fundamental understanding of different types of programmed cell death, which are physiologically critical processes that are involved in maintaining cellular homeostasis. These goals will be achieved using an integrative set of approaches that merges lipidomics, transcriptomics, and proteomics with structure-specific bioorthogonal lipids probes. This research program will focus on i) the function of distinct ceramides based on their structure during apoptosis and ii) the role of very long chain fatty acids in permeabilization of the membranes during necroptosis. A two component integration will be used for these studies: i) Determine substrate specificity of different ceramide synthases and investigate the function of specific ceramides using structure-specific probes and genetic perturbations, ii) determine the localization and interaction partners of very long chain fatty acids during necroptosis. The objectives will elucidate the function of lipids during cell death, providing a better fundamental understanding of these physiologically critical processes. The results from this work will shed light on the functional roles of specific lipids based on their precise chemical structure. They will specifically elucidate the role of individual ceramides and fatty acids on membrane permeabilization and their interaction with other biomolecules during apoptosis and necroptosis. This knowledge will open the door to novel studies investigating the impact of structural specificity on lipid function in cells.
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.
