Fundamental Studies on the Regulation and Interaction of Ceramides in Cellular Senescence and Cell Death

Suny At Buffalo, Amherst NY

Investigators

Abstract

Mammalian cells produce many types of lipids with different functions. As major components of biological membranes, lipids form barriers that define boundaries for cells and their internal compartments. Lipids also participate in distinct roles that signal essential cellular processes, such as cell division and programmed cell death. These functions can depend on the cellular localization of individual lipid types and other biological molecules with which they interact, as well as their cellular locale. Within this context, this project will apply biochemical, chemical biological, and analytical approaches to investigate the role of a specific lipid group (ceramides) in cellular senescence, a process that is defined by the cessation of cell division. The outcomes are expected to reveal novel fundamental biochemical mechanisms that regulate lipid function in cellular senescence and to have important implications for broader understanding of the role of ceramides in biological processes. The results should also be generalizable to other cell types. In addition, the project will provide for training of a globally competitive workforce across the educational spectrum, including the participation of students and teachers in research and scientific inquiry. Previous studies showed that ceramides are involved in apoptosis and replicative senescence. Replicative senescence is a state of cell cycle arrest that occurs when cells reach their proliferative capacity. It is a fundamental cellular process linked to organismal aging and wound healing, distinct from apoptosis. The pro-apoptotic activity of ceramides is well-studied; however, how ceramides function in replicative senescence remains unknown. The goal of this proposal is to elucidate the biochemical mechanisms that regulate the production, cellular localization, and function of ceramides in replicative senescence. To achieve this goal, proteins that interact with ceramides will be identified, the functional consequences of these interactions will be investigated, and biochemical mechanisms that regulate ceramide levels in senescence will be determined. The project will use an experimental design comparing senescent cell line models to investigate specific mechanisms by which ceramides are involved in replicative senescence. Further, for the first time, the study integrates multiple imaging, lipidomics, and perturbation-based methods to comprehensively resolve the regulation, trafficking, and protein interactions of ceramides at the organelle level during senescence. The knowledge obtained from this project will open the door to novel studies investigating the impact of cellular locale on the function of lipid species 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.