Request for Funding

Medical Student Research Fellowship for Summer 2001

Mentor:     Sandy Hofmann

Department:     Internal Medicine/Hamon Center for Therapeutic Oncology Research

Room number: NB8.104

Mail Code: 8593

Phone number: 8-4911

E-mail: Sandra.Hofmann@UTSouthwestern.edu

Project title: Phenotypic and Biochemical Characterization of PPT2 Deficient Mice

Human subjects IRB approved project number (where applicable): n. a.

Animal subjects IRB approved project number (where applicable): 0433-00-08-1

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects)

Brief Description of Project:

PPT2 (palmitoyl-protein thioesterase-2) is a novel lysosomal fatty-acyl thioesterase recently characterized in the lab. In vitro, it hydrolyzes palmitoyl CoA but its substrates in vivo are unknown. Deficiency in PPT1 produces a neurodegenerative phenotype in mice and humans. We have recently produced mice with a targeted deletion in PPT2. The aim of the project will be to characterize any behavioral or neurological deficits in PPT2 deficient mice and to initiate metabolic labeling studies using tissues from these mice to uncover the physiological substrates for PPT2.

Previous Research Activities or Publications with Medical Students:

1. Camp, L.A., and Hofmann, S.L. Purification and Properties of a Palmitoyl-Protein Thioesterase that Cleaves Palmitate from H-Ras. J. Biol. Chem. 268: 22566-22574 (1993).

2. Camp, L.A., Verkruyse, L.A., Afendis, S.J., Slaughter, C.S. and Hofmann, S.L. Molecular Cloning and Expression of Palmitoyl-Protein Thioesterase. J. Biol. Chem. 269: 23212-23219 (1994).

3. Vesa, J., Hellsten, E., Verkruyse, L. A., Camp, L. A., Rapola, J., Santavuori, P., Hofmann, S.L., and Peltonen, L. Mutations in the Palmitoyl Protein Thioesterase Gene Causing Infantile Neuronal Ceroid Lipofuscinosis. Nature 376: 584-587 (1995).

4. Hepler, J.R., Biddlecome, G.H., Kleuss, C., Camp, L.A., Hofmann, S.L., Ross, E.M., and Gilman, A.G. Functional Importance of the Amino Terminus of Gq?. J. Biol. Chem. 271: 496-504 (1996) .

5. Verkruyse, L.A. and Hofmann, S.L. Lysosomal Targeting of Palmitoyl-Protein Thioesterase. J. Biol. Chem. 271: 15831-15836 (1996).

6. Lu, J.-Y., Verkruyse, L.A., and Hofmann, S.L. Lipid Thioesters Derived from Acylated Proteins Accumulate in Infantile Neuronal Ceroid Lipofuscinosis: Correction of the Defect in Lymphoblasts by Recombinant Palmitoyl-Protein Thioesterase. Proc. Natl. Acad. Sci. U.S.A. 93: 10046-10050 (1996).

7. Verkruyse, L.A., Natowicz, M.R, and Hofmann, S.L. Palmitoyl-Protein Thioesterase Deficiency in Fibroblasts of Individuals with Infantile Neuronal Ceroid Lipofuscinosis and I-Cell Disease. Biochim. Biophys. Acta 1361:1-5 (1997).

8. Camp, L.A. and Hofmann, S.L. Assay and Isolation of a Palmitoyl-Protein Thioesterase from Bovine Brain Using Palmitoylated H-Ras as a Substrate. Meth. Enzymol. 250:336-347 (1995).

9. Hofmann, S.L., Lee, L.A., Lu, J.-Y., and Verkruyse, L.A. Palmitoyl-Protein Thioesterase and the Molecular Pathogenesis of Infantile Neuronal Ceroid Lipofuscinosis. Neuropediatrics 28: 27-30 (1997).

10. Hofmann, S.L., and Verkruyse, L.A. Fatty Acid Analysis of Protein-Derived Lipid Thioesters Isolated from Palmitoyl-Protein Thioesterase-Deficient Cells. Chapter 17, in Protein Lipidation Protocols, Methods in Molecular Biology 116:220-228 (1999).

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