There has been a recent explosion in the study of lipid mediated signal transduction and cell regulation. The over-riding paradigm has evolved from a reductionist approach and has focused on modular signaling whereby one stimulus regulates one enzyme resulting in the generation of one active molecule. However, the complexity of lipid metabolism far exceeds a simple collection of individual signaling modules such that one agonist may regulate several enzymes or the bioactive product of one enzyme (e.g. ceramide) may serve as a substrate for another enzyme generating a different bioactive molecule (such as diacylglycerol or sphingosine). Thus, we hypothesize that the complexity of lipid metabolism serves to provide a highly regulated and coordinated network of bioactive molecules with distinct and overlapping functions. This network then serves to integrate and coordinate complex responses of cells to various agents and environmental stimuli. This proposal will test the specific hypothesis that the sphingolipid sub-universe of cell regulation in S. cerevisiae constitutes a relatively discrete domain that allows the elucidation of biochemical regulation as well as integrative approaches. We propose that a combined reductionist and integrative mathematical and systems biology approach generates novel insights into lipid-mediated cell regulation and allows the dissection of specific pathways mechanistically and functionally... Thus, we aim to 1. Develop an integromics approach in order to dissect specific sphingolipid-mediated pathways in S. cerevisiae in response to specific perturbations of sphingolipid metabolism;2. Develop an advanced model of yeast sphingolipid metabolism that focuses on distinguishing individual ceramide species;and 3. Establish specific pathways of sphingolipid-mediated cell regulation. These studies will lay the groundwork for a "global" model of sphingolipid metabolism in which we may be able to predict specific metabolic and transcriptional responses that are regulated by individual sphingolipids. Subsequently, such an approach may allow us to predict the overall genetic response to a specific "configuration" of sphingolipid levels. This model system could then serve as a conceptual and practical platform to extend our hypotheses to other lipid classes, followed by other aspects of regulated metabolism (metabolomic level). Such approaches will prove critical in understanding the intricate, multi-level regulation of human pathobiology where bioactive lipids play key roles in such diseases as diabetes, neurodegeneration, cancer, and inflammation.

Public Health Relevance

The metabolism of lipids is very complex yet it is critical as many lipids are functional molecules that affect the function of the cell and the body, and are involved in diseases such as diabetes, neurodegeneration, cancer, and inflammation. We have assembled a team of biochemists, molecular biologists, mathematical modelers, and system biologists in order to define novel approaches by which we can organize our knowledge on lipid metabolism and enable research that deciphers the function of individual lipids.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM063265-12
Application #
8251116
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (02))
Program Officer
Chin, Jean
Project Start
2001-04-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
12
Fiscal Year
2012
Total Cost
$412,983
Indirect Cost
$101,133
Name
State University New York Stony Brook
Department
Family Medicine
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Spincemaille, Pieter; Matmati, Nabil; Hannun, Yusuf A et al. (2014) Sphingolipids and mitochondrial function in budding yeast. Biochim Biophys Acta 1840:3131-7
Swinnen, Erwin; Wilms, Tobias; Idkowiak-Baldys, Jolanta et al. (2014) The protein kinase Sch9 is a key regulator of sphingolipid metabolism in Saccharomyces cerevisiae. Mol Biol Cell 25:196-211
Vilaca, Rita; Silva, Elisio; Nadais, Andre et al. (2014) Sphingolipid signalling mediates mitochondrial dysfunctions and reduced chronological lifespan in the yeast model of Niemann-Pick type C1. Mol Microbiol 91:438-51
Montefusco, David J; Matmati, Nabil; Hannun, Yusuf A (2014) The yeast sphingolipid signaling landscape. Chem Phys Lipids 177:26-40
Chen, Po-Wei; Fonseca, Luis L; Hannun, Yusuf A et al. (2013) Coordination of rapid sphingolipid responses to heat stress in yeast. PLoS Comput Biol 9:e1003078
Matmati, Nabil; Metelli, Alessandra; Tripathi, Kaushlendra et al. (2013) Identification of C18:1-phytoceramide as the candidate lipid mediator for hydroxyurea resistance in yeast. J Biol Chem 288:17272-84
Voit, Eberhard O (2013) Characterizability of metabolic pathway systems from time series data. Math Biosci 246:315-25
Rachidi, Saleh M; Qin, Tingting; Sun, Shaoli et al. (2013) Molecular profiling of multiple human cancers defines an inflammatory cancer-associated molecular pattern and uncovers KPNA2 as a uniform poor prognostic cancer marker. PLoS One 8:e57911
Montefusco, David J; Chen, Lujia; Matmati, Nabil et al. (2013) Distinct signaling roles of ceramide species in yeast revealed through systematic perturbation and systems biology analyses. Sci Signal 6:rs14
Montefusco, David J; Newcomb, Benjamin; Gandy, Jason L et al. (2012) Sphingoid bases and the serine catabolic enzyme CHA1 define a novel feedforward/feedback mechanism in the response to serine availability. J Biol Chem 287:9280-9

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