The mechanisms by which eukaryotic cells control the synthesis of membrane lipids in coordination with ongoing membrane biogenesis are not well understood. Yet phospholipids, particularly inositol-containing phospholipids, have been implicated in complex signaling processes which play a role in controlling cell growth and proliferation in higher eukaryotes. Yeast cells synthesize a typically eukaryotic mixture of phospholipids, using pathways which are similar to those in higher eukaryotes. This organism can be manipulated using powerful molecular genetics and analyzed using new genome-wide techniques. The proposed analysis will produce a detailed model of the relative inputs and interactions of multiple signaling pathways influencing phospholipid metabolism, an essential cellular process which itself produces signals that feedback to produce autoregulatory loops and influence other metabolism, membrane trafficking and signal transduction pathways. A genetic assessment will be conducted of the combinatorial inputs and interactions of cellular processes influencing, and influenced by, phospholipid metabolism in yeast including, membrane trafficking, silencing and signaling. Methods which allow quantitative determination of 100 or more metabolites in a single experiment will be used to assess lipid metabolism in selected mutants and their suppressors in order to identify metabolic signals influencing this regulation. Microarray analysis will be used to explore the kinetics of gene expression, genome wide, in response to changes in lipid metabolism. Relevance: An understanding of the regulation of lipid metabolism is critical in dealing with chronic conditions such as obesity, diabetes, and atherosclerosis. Yeast is an excellent model system for such studies since the relevant pathways are common to yeast and mammals and the major enzymes are homologous, ensuring that insights derived from yeast will generate knowledge relevant to human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM019629-38
Application #
7760854
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (02))
Program Officer
Chin, Jean
Project Start
1987-09-01
Project End
2012-03-31
Budget Start
2010-02-01
Budget End
2012-03-31
Support Year
38
Fiscal Year
2010
Total Cost
$502,485
Indirect Cost
Name
Cornell University
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Gaspar, Maria L; Chang, Yu-Fang; Jesch, Stephen A et al. (2017) Interaction between repressor Opi1p and ER membrane protein Scs2p facilitates transit of phosphatidic acid from the ER to mitochondria and is essential for INO1 gene expression in the presence of choline. J Biol Chem 292:18713-18728
Barneda, David; Planas-Iglesias, Joan; Gaspar, Maria L et al. (2015) The brown adipocyte protein CIDEA promotes lipid droplet fusion via a phosphatidic acid-binding amphipathic helix. Elife 4:e07485
Han, Sungwon; Binns, Derk D; Chang, Yu-Fang et al. (2015) Dissecting seipin function: the localized accumulation of phosphatidic acid at ER/LD junctions in the absence of seipin is suppressed by Sei1p(?Nterm) only in combination with Ldb16p. BMC Cell Biol 16:29
Henry, Susan A; Gaspar, Maria L; Jesch, Stephen A (2014) The response to inositol: regulation of glycerolipid metabolism and stress response signaling in yeast. Chem Phys Lipids 180:23-43
Hofbauer, Harald F; Schopf, Florian H; Schleifer, Hannes et al. (2014) Regulation of gene expression through a transcriptional repressor that senses acyl-chain length in membrane phospholipids. Dev Cell 29:729-39
Lee, Sojin; Gaspar, Maria L; Aregullin, Manuel A et al. (2013) Activation of protein kinase C-mitogen-activated protein kinase signaling in response to inositol starvation triggers Sir2p-dependent telomeric silencing in yeast. J Biol Chem 288:27861-71
Aung, Hnin W; Henry, Susan A; Walker, Larry P (2013) Revising the Representation of Fatty Acid, Glycerolipid, and Glycerophospholipid Metabolism in the Consensus Model of Yeast Metabolism. Ind Biotechnol (New Rochelle N Y) 9:215-228
Henry, Susan A; Kohlwein, Sepp D; Carman, George M (2012) Metabolism and regulation of glycerolipids in the yeast Saccharomyces cerevisiae. Genetics 190:317-49
Villa-GarcĂ­a, Manuel J; Choi, Myung Sun; Hinz, Flora I et al. (2011) Genome-wide screen for inositol auxotrophy in Saccharomyces cerevisiae implicates lipid metabolism in stress response signaling. Mol Genet Genomics 285:125-49
Gaspar, Maria L; Hofbauer, Harald F; Kohlwein, Sepp D et al. (2011) Coordination of storage lipid synthesis and membrane biogenesis: evidence for cross-talk between triacylglycerol metabolism and phosphatidylinositol synthesis. J Biol Chem 286:1696-708

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