The National Institute of Diabetes & Digestive & Kidney Diseases

Sphingolipids are a structurally diverse class of molecules with potent cell signaling activities. They play key roles for the development and functioning of the cardiovascular system, in immunity and inflammation and in the nervous system. Our work is aimed at defining the normal functions of sphingolipids and understanding their roles in diseases.

Glycosphingolipids (GSLs) are found in the outer leaflet of the plasma membrane and are concentrated in specialized signaling structures called rafts. They are particularly abundant in neuronal cells in the form of gangliosides (sialic acid containing GSLs). Through genetic disruption of genes that encode synthetic enzymes for GSLs, we have created a series of mice that express limited glycosphingolipid structures. We are using these mice to discover the function of GSLs. When the cellular machinery responsible for GSL degradation is defective, GSL storage diseases result in which profound neurodegeneration occurs. Examples are Tay-Sachs and Gaucher diseases. We are attempting to understand how the accumulation of GSLs cause neurodegeneration through the study of animal models of the diseases.

Sphingosine-1-phosphate is a bioactive sphingolipid metabolite that binds to a family of G-protein-coupled receptors, known as S1P or EDG receptors. Stimulation of S1P receptors triggers diverse cellular effects. By studing mice with mutations in S1P receptors and the enzymes that produce sphingosine-1-phosphate we have determined that the S1P metabolic signaling system is involved in remarkably diverse physiological activities. These include development of the nervous and vascular systems; the regulation of lymphocyte trafficing and immunity.

Clinical Protocols

• Investigation of Neurodegeneration in Glycosphingolipid Storage Disorders, 02-DK-0107
  

Kono M, Belyantseva IA, Skoura A, Frolenkov GI, Starost MF, Dreier JL, Lidington D, Bolz SS, Friedman TB, Hla T, Proia RL Deafness and stria vascularis defects in S1P2 receptor null mice. J Biol Chem, 2007. [Full Text/Abstract]

Rummel A, Eichner T, Weil T, Karnath T, Gutcaits A, Mahrhold S, Sandhoff K, Proia RL, Acharya KR, Bigalke H, Binz T Identification of the protein receptor binding site of botulinum neurotoxins B and G proves the double-receptor concept. Proc Natl Acad Sci U S A(104): 359-64, 2007. [Full Text/Abstract]

Olivera A, Mizugishi K, Tikhonova A, Ciaccia L, Odom S, Proia RL, Rivera J The Sphingosine Kinase-Sphingosine-1-Phosphate Axis Is a Determinant of Mast Cell Function and Anaphylaxis. Immunity, 2007. [Full Text/Abstract]

Olivera A, Urtz N, Mizugishi K, Yamashita Y, Gilfillan AM, Furumoto Y, Gu H, Proia RL, Baumruker T, Rivera J IgE-dependent activation of sphingosine kinases 1 and 2 and secretion of sphingosine 1-phosphate requires Fyn kinase and contributes to mast cell responses. J Biol Chem (281): 2515-25, 2006. [Full Text/Abstract]

Kohno M, Momoi M, Oo ML, Paik JH, Lee YM, Venkataraman K, Ai Y, Ristimaki AP, Fyrst H, Sano H, Rosenberg D, Saba JD, Proia RL, Hla T Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol Cell Biol (26): 7211-23, 2006. [Full Text/Abstract]

Kono M, Dreier JL, Ellis JM, Allende ML, Kalkofen DN, Sanders KM, Bielawski J, Bielawska A, Hannun YA, Proia RL Neutral ceramidase encoded by the Asah2 gene is essential for the intestinal degradation of sphingolipids. J Biol Chem (281): 7324-31, 2006. [Full Text/Abstract]

Kabashima K, Haynes NM, Xu Y, Nutt SL, Allende ML, Proia RL, Cyster JG Plasma cell S1P1 expression determines secondary lymphoid organ retention versus bone marrow tropism. J Exp Med(203): 2683-90, 2006. [Full Text/Abstract]

Yamashita T, Allende ML, Kalkofen DN, Werth N, Sandhoff K, Proia RL Conditional LoxP-flanked glucosylceramide synthase allele controlling glycosphingolipid synthesis. Genesis (43): 175-80, 2005. [Full Text/Abstract]

Mizugishi K, Yamashita T, Olivera A, Miller GF, Spiegel S, Proia RL Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol (25): 11113-21, 2005. [Full Text/Abstract]

Yamashita T, Wu YP, Sandhoff R, Werth N, Mizukami H, Ellis JM, Dupree JL, Geyer R, Sandhoff K, Proia RL Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon-glial interactions. Proc Natl Acad Sci U S A (102): 2725-30, 2005. [Full Text/Abstract]

Osawa Y, Hannun YA, Proia RL, Brenner DA Roles of AKT and sphingosine kinase in the antiapoptotic effects of bile duct ligation in mouse liver. Hepatology (42): 1320-8, 2005. [Full Text/Abstract]

Proia RL Wu YP Blood to brain to the rescue. J Clin Invest (113): 1108-10, 2004. [Full Text/Abstract]

Wu YP Proia RL Deletion of macrophage-inflammatory protein 1 alpha retards neurodegeneration in Sandhoff disease mice. Proc Natl Acad Sci U S A (101): 8425-30, 2004. [Full Text/Abstract]

Allende ML Dreier JL Mandala S Proia RL Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J Biol Chem (279): 15396-401, 2004. [Full Text/Abstract]

Proia RL Gangliosides help stabilize the brain. Nat Genet (36): 1147-1148, 2004. [Full Text/Abstract]

Proia RL Gangliosides help stabilize the brain. Nat Genet (36): 1147-8, 2004. [Full Text/Abstract]

Matloubian M Lo CG Cinamon G Lesneski MJ Xu Y Brinkmann V Allende ML Proia RL Cyster JG Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature (427): 355-60, 2004. [Full Text/Abstract]

Zhou D, Mattner J, Cantu Iii C, Schrantz N, Yin N, Gao Y, Sagiv Y, Hudspeth K, Wu Y, Yamashita T, Teneberg S, Wang D, Proia R, Levery SB, Savage PB, Teyton L, Bendelac A Lysosomal Glycosphingolipid Recognition by NKT cells. Science , 2004. [Full Text/Abstract]

Zhou D, Mattner J, Cantu C 3rd, Schrantz N, Yin N, Gao Y, Sagiv Y, Hudspeth K, Wu YP, Yamashita T, Teneberg S, Wang D, Proia RL, Levery SB, Savage PB, Teyton L, Bendelac A Lysosomal glycosphingolipid recognition by NKT cells. Science (306): 1786-9, 2004. [Full Text/Abstract]

Allende ML, Sasaki T, Kawai H, Olivera A, Mi Y, Van Echten-Deckert G, Hajdu R, Rosenbach M, Keohane CA, Mandala S, Spiegel S, Proia RL Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. J Biol Chem , 2004. [Full Text/Abstract]

Allende ML, Sasaki T, Kawai H, Olivera A, Mi Y, van Echten-Deckert G, Hajdu R, Rosenbach M, Keohane CA, Mandala S, Spiegel S, Proia RL Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. J Biol Chem (279): 52487-92, 2004. [Full Text/Abstract]

Cinamon G, Matloubian M, Lesneski MJ, Xu Y, Low C, Lu T, Proia RL, Cyster JG Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nat Immunol (5): 713-20, 2004. [Full Text/Abstract]

Cinamon G Matloubian M Lesneski MJ Xu Y Low C Lu T Proia RL Cyster JG Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nat Immunol (5): 713-20, 2004. [Full Text/Abstract]

Paik JH, Skoura A, Chae SS, Cowan AE, Han DK, Proia RL, Hla T Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization. Genes Dev (18): 2392-403, 2004. [Full Text/Abstract]

Paik JH Skoura A Chae SS Cowan AE Han DK Proia RL Hla T Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization. Genes Dev , 2004. [Full Text/Abstract]

Kono M Mi Y Liu Y Sasaki T Allende ML Wu YP Yamashita T Proia RL The sphingosine-1-phosphate receptors S1P1, S1P2, and S1P3 function coordinately during embryonic angiogenesis. J Biol Chem (279): 29367-73, 2004. [Full Text/Abstract]

Jolly PS Bektas M Olivera A Gonzalez-Espinosa C Proia RL Rivera J Milstien S Spiegel S Transactivation of Sphingosine-1-Phosphate Receptors by Fc{varepsilon}RI Triggering Is Required for Normal Mast Cell Degranulation and Chemotaxis. J Exp Med (199): 959-970, 2004. [Full Text/Abstract]

Yamashita T Hashiramoto A Haluzik M Mizukami H Beck S Norton A Kono M Tsuji S Daniotti JL Werth N Sandhoff R Sandhoff K Proia RL Enhanced insulin sensitivity in mice lacking ganglioside GM3. Proc Natl Acad Sci U S A (100): 3445-9, 2003. [Full Text/Abstract]

Allende ML Yamashita T Proia RL G-protein-coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation. Blood (102): 3665-7, 2003. [Full Text/Abstract]

Kolter T Proia RL Sandhoff K Combinatorial ganglioside biosynthesis. J Biol Chem (277): 25859-62, 2002. [Full Text/Abstract]

Allende ML Proia RL Lubricating cell signaling pathways with gangliosides. Curr Opin Struct Biol (12): 587-92, 2002. [Full Text/Abstract]

Myerowitz R Lawson D Mizukami H Mi Y Tifft CJ Proia RL Molecular pathophysiology in Tay-Sachs and Sandhoff diseases as revealed by gene expression profiling. Hum Mol Genet (11): 1343-50, 2002. [Full Text/Abstract]

Kawai H Allende ML Wada R Kono M Sango K Deng C Miyakawa T Crawley JN Werth N Bierfreund U Sandhoff K Proia RL Mice expressing only monosialoganglioside GM3 exhibit lethal audiogenic seizures. J Biol Chem (276): 6885-8, 2001. [Full Text/Abstract]

Liu Y Wada R Yamashita T Mi Y Deng CX Hobson JP Rosenfeldt HM Nava VE Chae SS Lee MJ Liu CH Hla T Spiegel S Proia RL Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest (106): 951-61, 2000. [Full Text/Abstract]

Wada R Tifft CJ Proia RL Microglial activation precedes acute neurodegeneration in Sandhoff disease and is suppressed by bone marrow transplantation. Proc Natl Acad Sci U S A (97): 10954-9, 2000. [Full Text/Abstract]

Tifft CJ Proia RL Stemming the tide: glycosphingolipid synthesis inhibitors as therapy for storage diseases. Glycobiology (10): 1249-58, 2000. [Full Text/Abstract]

Yamashita T Wada R Sasaki T Deng C Bierfreund U Sandhoff K Proia RL A vital role for glycosphingolipid synthesis during development and differentiation. Proc Natl Acad Sci U S A (96): 9142-7, 1999. [Full Text/Abstract]

Sheikh KA Sun J Liu Y Kawai H Crawford TO Proia RL Griffin JW Schnaar RL Mice lacking complex gangliosides develop Wallerian degeneration and myelination defects. Proc Natl Acad Sci U S A (96): 7532-7, 1999. [Full Text/Abstract]