The overall goals of this research proposal are to define specific pathways of sphingolipid metabolism, define specific roles, define mechanisms, and help place the field of bioactive lipids on solid mechanistic grounds. Based on strong ongoing data, we propose the overall hypothesis that individual enzymes of ceramide metabolism serve as transducers of specific inputs, and the product bioactive sphingolipids function to mediate key responses. This proposal will develop this paradigm in the case of the DNA damage response and other stimuli activating neutral sphingomyelinases in distinct compartments leading to formation of ceramide which acts primarily in a cell cycle checkpoint. We propose the following specific goals: 1. What are the mechanisms involved in induction of nSMase2 and Isc1? 2. How are nSMase2 and Isc1 activated in the nucleus? Is there a specific role for nuclear PIP2? 3. Define mechanisms of regulation and the structure of neutral sphingomyelinases 4. What is the structure of lipids in the nucleus? 5. What is the specific function of nSMase2 (and Isc1) in checkpoints? 6. Do nuclear phosphatases mediate the action of nuclear ceramide; what are the mechanisms involved? 7. Define parallel pathways of bioactive sphingolipids in yeast. Taken together, we endeavor to advance our understanding of bioactive sphingolipids and reduce its complexities to manageable and specific components that promise to shed important light on how these specific pathways function, and their specific roles in stress responses. The ongoing results are defining a totally unexpected role for neutral sphingomyelinases in the eukaryotic DNA damage response through a nuclear lipid-mediated pathway.

Public Health Relevance

Sphingolipids are a class of fatty molecules that have been thought to serve primarily as structural molecules in formation of cell membranes. Our work identified specific functions for individual sphingolipids, thus leading to their appreciation as 'bioactive molecules'. In this proposal we focus on key enzymes of sphingolipid metabolism with important functions in cell stress responses. We define a critical role in their roles in the integrity of their DNA and how cells respond to DNA damage. In the process of defining these pathways and mechanisms, we tackle some of the most recalcitrant problems in understanding these pathways.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZGM1)
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Ainsztein, Alexandra M
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State University New York Stony Brook
Family Medicine
Schools of Medicine
Stony Brook
United States
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Chen, Jennifer Y; Newcomb, Benjamin; Zhou, Chan et al. (2017) Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells. Sci Rep 7:44867
Airola, Michael V; Shanbhogue, Prajna; Shamseddine, Achraf A et al. (2017) Structure of human nSMase2 reveals an interdomain allosteric activation mechanism for ceramide generation. Proc Natl Acad Sci U S A 114:E5549-E5558
Senkal, Can E; Salama, Mohamed F; Snider, Ashley J et al. (2017) Ceramide Is Metabolized to Acylceramide and Stored in Lipid Droplets. Cell Metab 25:686-697
Xu, Ruijuan; Wang, Kai; Mileva, Izolda et al. (2016) Alkaline ceramidase 2 and its bioactive product sphingosine are novel regulators of the DNA damage response. Oncotarget 7:18440-57
Yi, Jae Kyo; Xu, Ruijuan; Jeong, Eunmi et al. (2016) Aging-related elevation of sphingoid bases shortens yeast chronological life span by compromising mitochondrial function. Oncotarget 7:21124-44
Clarke, Christopher J; Shamseddine, Achraf A; Jacob, Joseph J et al. (2016) ATRA transcriptionally induces nSMase2 through CBP/p300-mediated histone acetylation. J Lipid Res 57:868-81
Begum, Mahfuj A; Shi, Xiao-Xiao; Tan, Ye et al. (2016) Molecular Characterization of Rice OsLCB2a1 Gene and Functional Analysis of its Role in Insect Resistance. Front Plant Sci 7:1789
Carroll, Brittany L; Pulkoski-Gross, Michael J; Hannun, Yusuf A et al. (2016) CHK1 regulates NF-?B signaling upon DNA damage in p53- deficient cells and associated tumor-derived microvesicles. Oncotarget 7:18159-70
Wu, Song; Hannun, Yusuf (2016) The importance of extrinsic factors in the development of cancers. Mol Cell Oncol 3:e1143079
Wu, Song; Powers, Scott; Zhu, Wei et al. (2016) Substantial contribution of extrinsic risk factors to cancer development. Nature 529:43-7

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