Sphingolipids are integral components of all eukaryotic cell membranes; many of them like ceramide, sphingosine, sphingosine-1 -phosphate (S-1-P) are also bioactive lipids regulating cellular functions ranging from apoptosis to angiogenesis. Our long-term goal is to comprehensively understand functions of enzymes that control normal sphingolipid metabolism and their integration into other pathways involved in cell growth, differentiation and signaling. To address our goal, we study enzymes of sphingolipid biosynthesis using Drosophila as a model system. This proposal is based on the observation that sphingolipid metabolism plays an important role in survival of photoreceptors. Our findings show that decreasing ceramide levels by genetic modulation of the sphingolipid biosynthetic pathway suppresses retinal degeneration in a set of phototransduction mutants. Recent studies in human patients show that mutations in enzymes of ceramide metabolism cause Retinitis Pigmentosa and Hereditary Sensory Neuropathy. Based on these findings, the focus of this project is to understand how ceramide metabolism contributes to maintenance of photoreceptor homeostasis and other cellular functions. We will elucidate in vivo functions of three enzymes that decrease ceramide levels - ceramidase that converts ceramide to sphingosine, ceramide kinase that converts ceramide to ceramide-1-phosphate and sphingosine kinase that converts sphingosine to S-1-P. While ceramide and sphingosine are pro-death, S-1-P is pro-growth. The relative level of these antagonistic metabolites, regulated by the biosynthetic enzymes, determines whether a cell survives or dies.
The specific aims of the project are (1) study components downstream of ceramidase in suppression of retinal degeneration and elucidate ceramidase function using a mutant (2) generate ceramide kinase mutant and transgenic flies to study its functions (3) generate and analyze mutant and transgenic flies to define the role of sphingosine kinase in regulating levels of sphingolipid metabolites.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016469-04
Application #
7386649
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Mariani, Andrew P
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$347,934
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Rahman, Motiur; Nirala, Niraj K; Singh, Alka et al. (2014) Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase ? and regulates complex V activity. J Cell Biol 206:289-305
Kunduri, Govind; Yuan, Changqing; Parthibane, Velayoudame et al. (2014) Phosphatidic acid phospholipase A1 mediates ER-Golgi transit of a family of G protein-coupled receptors. J Cell Biol 206:79-95
Nirala, Niraj K; Rahman, Motiur; Walls, Stanley M et al. (2013) Survival response to increased ceramide involves metabolic adaptation through novel regulators of glycolysis and lipolysis. PLoS Genet 9:e1003556
Yuan, Changqing; Rao, Raghavendra Pralhada; Jesmin, Nahid et al. (2011) CDase is a pan-ceramidase in Drosophila. Mol Biol Cell 22:33-43
Yonamine, Ikuko; Bamba, Takeshi; Nirala, Niraj K et al. (2011) Sphingosine kinases and their metabolites modulate endolysosomal trafficking in photoreceptors. J Cell Biol 192:557-67
Dasgupta, Ujjaini; Bamba, Takeshi; Chiantia, Salvatore et al. (2009) Ceramide kinase regulates phospholipase C and phosphatidylinositol 4, 5, bisphosphate in phototransduction. Proc Natl Acad Sci U S A 106:20063-8
Wang, Xin; Rao, Raghavendra Pralhada; Kosakowska-Cholody, Teresa et al. (2009) Mitochondrial degeneration and not apoptosis is the primary cause of embryonic lethality in ceramide transfer protein mutant mice. J Cell Biol 184:143-58
Acharya, Jairaj K; Dasgupta, Ujjaini; Rawat, Satinder S et al. (2008) Cell-nonautonomous function of ceramidase in photoreceptor homeostasis. Neuron 57:69-79
Sanxaridis, Parthena D; Cronin, Michelle A; Rawat, Satinder S et al. (2007) Light-induced recruitment of INAD-signaling complexes to detergent-resistant lipid rafts in Drosophila photoreceptors. Mol Cell Neurosci 36:36-46
Rao, Raghavendra Pralhada; Yuan, Changqing; Allegood, Jeremy C et al. (2007) Ceramide transfer protein function is essential for normal oxidative stress response and lifespan. Proc Natl Acad Sci U S A 104:11364-9