B.S., Bates College, 1976
Ph.D., University of Texas Southwestern Medical Center, 1981
Research Statement
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
Back to Top
Selected Publications
1. 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]
2. 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]
3. 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]
4. 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]
5. 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]
6. 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]
7. 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]
8. 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]
9. 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]
10. 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]
1 2 3 4 Next >>
