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Thomas A. Grigliatti, PhD (B.Sc. Santa Clara University; M.Sc. Calif. State Univ., S. F. Cell & Molecular Biology; Ph.D. UBC, Genetics) RESEARCH SUMMARY: Autism is a complex disorder. Hence, there will be several different genes that are altered to either cause or increase susceptibility to the disorder. Therefore, it is important to identify the aberrant genes (mutant alleles), their protein products and to define the roles of each of these proteins in altering normal physiological events.
We have several different platforms available for target validation, drug lead-compound identification, and validation of any potential drug leads. Since this is a simple summary, we present only one brief example. We have the ability to reconstitute any portion of the mammalian (human) proteome (up to 10 genes and their products) in transformed insect cell-lines (the advantages of insect cells as a host for the reconstituted portion of the proteome are many). The function and interaction of the expressed human proteins is indistinguishable from their action in vivo (in human tissues). These technologies allow us to examine in detail the function of any physiological process, and to define the genes/proteins that are both necessary and sufficient for proper function of multi-component complexes, physiological pathways, or combinations thereof. Having defined the components and their interactions, we can then analyze specific, naturally occuring mutations, which exist within the human population, in any of the components and define the extent to which each mutation alters the physiological process. This defines the biochemical relevance of these variant forms of the genes (mutant alleles) and their protein products, that occur naturally within the human population. Once the biochemical relevance is defined, we then go back to patient analysis and demonstrate clinical relevance and connection to a specific dysgenic phenotype. From this we can easily make diagnostic tools that allow us to determine whether an individual has this specific genetic polymorphism. In addition, and perhaps more importantly, these stable cell lines expressing a defined portion of the human proteome serve as stable platforms for high-throughput screening for drug lead compounds, target validation, and for the characterization, testing and development of new drugs to treat the disorder. We are focusing our efforts on several different candidate loci (genes) that may be associated with various forms of autism and autism spectrum disorders. PEOPLE WHO WORK IN HIS LAB: Research Associates RELEVANT PUBLICATIONS: Hegedus, D.D., Pfeifer, T A., Kennard, M.L., Gabathuler, W.A., Jeffries, D.A., Theilmann, D.A., and Grigliatti, T. A. Intergenic Differences in the Expression of Human Melanotransferrin in Insect Cell Lines. Protein Expression and Purification 15: 296-307 1999.
Lloyd, V. K., Sinclair, D., A., & Grigliatti, T. A. Genomic Imprinting and Position-effect Variegation in Drosophila melanogaster . Genetics 151:1503-1516. 1999.
Mottus, R., Sobel, R., & Grigliatti, T. A. Mutations in a Histone Deacetylase Gene Suppress Position-effect Variegation in Drosophila. Genetics 154: 657-668. 2000. Grigliatti, T. A., Pfeifer, T., & Meister, G. TAC-TICS: Transposon-based Insect Control Systems. In: Enhancing Biocontrol and Handling Risks. Eds. M. Vurro, Gressel, J., Butt, T., Harman, D., Nuss, D., Sands, D., St. Leger, R. (eds). NATO Science Series, IOS Press, Amsterdam, The Netherlands. Vol. 339, pp 201-216. 2001.
Pfeifer, T. A., Guarna, M. M., Kwan, E. M. Lesnicki, G., Theilmann, D. A., Grigliatti, T. A. & Kilburn D. G. Expression analysis of a modified FactorX in stable insect cell lines. Protein Expression and Purification 23: 233-241. 2001.
Ner ,S. S., Bland, T., Perez-Paralle, M. L., Grigliatti, T. A., Becker, P. B., & Travers, A. A. HMG-D and Histone H1 Interplay during Chromatin Assembly and Early embryogenesis. J. Biological Chemistry 276: 37569-37576. 2001.
Ner. S.S, Harrington, M., & Grigliatti, T. A. A Role for the Drosophila Su(var)3-9 Protein in Chromatin Organization at the Histone Gene Cluster and a Molecular Basis for Suppression of Position-effect Variegation. Genetics 162: 1763-1774. 2002.
Harvey, L., Reid, R.E., Ma, C., Knight, P.J.K., Pfeifer, T.A., & Grigliatti, T. A.. Human Genetic Variations in the 5HT2A Receptor: A Single Nucleotide Polymorphism Identified with Altered Response to Clozapine.Pharmacogenetics, 13: 107-118. 2003. ___
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