Project Summary:

Synaptic transmission requires specific lipid composition in vesicle and plasma membranes, and is tightly regulated by lipid-based signaling mechanisms. Of particular interest is the involvement of sterol/sphingolipid rich lipid microdomains (lipid rafts). Many aspects of these domains remain highly controversial, including how to define them, their size, lipid and protein composition, and biological relevance. Nevertheless, lipid microdomains in neuronal membranes have documented roles in regulating ion channels, localizing the synaptic vesicle exocytic machinery and modulating neurotransmitter receptors. Altered lipid domain organization and lipid mistrafficking/aggregation are also associated with several diseases including Niemann-Pick, Alzheimer's and lysosomal storage diseases. The central role sterol/sphingolipids may play in synaptic function and neurological disease dictates the need to understand the mechanisms of sterol/sphingolipid trafficking/signaling in neurons. The power of Drosophila genetics has proven to be an invaluable resource for modeling neurological diseases. Furthermore, the Drosophila neuromuscular junction (NMJ) is commonly employed for studying synaptic mechanisms, making this an ideal genetic system to better understand the requirement of sterol/sphingolipid microdomain function in regulating neurotransmission. The goals of our research are: (i), to determine the effects of disrupting sterol/sphingolipid metabolism on neuronal lipid trafficking/composition and lipid domain formation, (ii), to determine the requirement of sterol/sphingolipid rich domains in neurotransmission and protein trafficking in neurons, and (iii), to test if altered synaptic activity caused by changes in membrane lipid composition leads to age-progressive neurodegeneration. Our hypothesis is that sterol/sphingolipid microdomains are necessary for protein/membrane trafficking in the synapse and that disruption of these domains may be causative in neurodegeneration.

 

Education:

08/05	Ph.D., Department of Cell and Developmental Biology, The Univ. of North Carolina at Chapel Hill, Chapel Hill, NC. (Advisor: Vytas Bankaitis, Ph.D.) Thesis Title: “Function of Phosphatidylinositol Transfer Proteins from Saccharomyces cerevisiae to Mammals.”
09/97-08/00	Graduate Student, Department of Cell Biology The Univ. of Alabama at Birmingham, Birmingham, AL. (Advisor: Vytas Bankaitis, Ph.D)
12/95	B.S. Microbiology B.S. Environmental Science Auburn University, Auburn, AL

Publications:

1. Kearns, B.G., McGee, T.P., Mayinger, P., Gedvilaite, A., Phillips, S.E., Kagiwada, S., and Bankaitis, V.A. 1997. Essential role for diacylglycerol in protein transport from the yeast Golgi complex. Nature 387: 101-105.

 

2. Sha, B., Phillips, S.E., Bankaitis, V.A., and Luo, M. 1997. Crystallization and preliminary X-ray diffraction studies of the Saccharomyces cerevisiae phospholipid transfer protein complexed with phosphatidylcholine. Acta Crystallographica D 53:784-786.

 

3. Sha, B., Phillips, S.E., Bankaitis, V.A., and Luo, M. 1998.Crystal structure of the Saccharomyces cerevisiae phosphatidylinositol transfer protein Sec14p. Nature 391:506-510.

 

4. Jones, S.M., Alb, J.G., Phillips, S.E., Bankaitis, V.A., and Howell, K.E. 1998. A phosphatidylinositol-3-kinase and phosphatidylinositol transfer protein act synergistically in formation of constitutive transport vesicles from the trans-Golgi network. J. Biol. Chem. 273:10349-10354.

 

5. Phillips, S.E., Sha, B., Topalof, L., Xie, Z., Alb, J.G., Klenchin, V., Swigart, P., Cockcroft, S., Luo, M., Martin, T.F.J., and Bankaitis, V.A. 1999. Yeast Sec14p deficient in phosphatidylinositol transfer activity is functional in vivo. Molecular Cell. 4:187-197.

 

6. Pinxteren, J.A., Gomperts, B.D., Rogers, D., Phillips, S.E., Tatham, P.E., and Thomas, G.M. 2001 Phosphatidylinositol transfer proteins and protein kinase C make separate but non-interacting contributions to the phosphorylation state necessary for secretory competence in rat mast cells. Biochem J. 15:287-296.

 

7. Alb, J.G. Jr.*, Phillips, S.E.*, Rostand, K., Cui, X., Pinxteren, J., Cotlin, L., Manning, T., Guo, S., York, J.D., Sontheimer, H., Collawn, J.F., and Bankaitis, V.A. 2002. Genetic ablation of phosphatidylinositol transfer protein function in murine embryonic stem cells. Mol Biol Cell. 13:739-754.

 

8. Alb, J.G. Jr., Cortese, J.D., Phillips, S.E., Albin, R.L., Nagy, T.R., Hamilton, B.A., and Bankaitis, V.A. 2003. Mice lacking phosphatidylinositol transfer protein-alpha exhibit spinocerebellar degeneration, intestinal and hepatic steatosis, and hypoglycemia. J Biol. Chem. 278:33501-33518.

 

9. Bankaitis, V.A., Cortese, J., Phillips, S.E., and Alb, J.G. Jr. 2004. Phosphatidylinositol transfer protein function in the mouse. Advan. Enzyme Regul. 44:201-218.

 

10. Bankaitis, V.A., Phillips, S., Yanagisawa, L., Li, X., Routt, S., and Xie, Z. 2005. Phosphatidylinositol transfer protein function in the yeast Saccharomyces cerevisiae. Advan. Enzyme Regul. 45:155-170.

 

11. Phillips S.E., Vincent, P., Rizzieri, K.E., Schaaf, G., Bankaitis, V.A., and Gaucher, E.A. 2006. The diverse biological functions of phosphatidylinositol transfer proteins in eukaryotes. Crit Rev Biochem Mol Biol. Jan-Feb;41(1):21-49.

 

12. Phillips, S.E., Ile, K., Boukhelifa, M., Huijbregts, R. and Bankaitis, V.A. 2006. Specific and nonspecific membrane binding determinants cooperate in targeting phosphatidylinositol transfer protein b-isoform to the murine trans-Golgi network. Mol. Biol. Cell. Jun;17(6):2498-512.

 

13. Ryan, M.R., Temple, B.R.S., Phillips, S.E., and Bankaitis, V.A. 2007. Conformational dynamics of the major yeast phosphatidylinositol transfer protein Sec14p: Insights into the mechanisms of phospholipid exchange and diseases of Sec14p-like protein deficiencies. Mol. Biol. Cell May;18(5):1928-42.

 

14. Alb, J.G., Phillips, S.E., Wilfley, L.R., Philpot, B.D., and Bankaitis, V.A. 2007. Functional dissection of the relationships between phosphatidylinositol transfer protein alpha activity and the complex pathologies of PITPalpha nullizygous mice. J. Lipid Res. May 24 (Epub ahead of print).

 

* denotes co-first authors