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David Saffen, Ph.D.  Associate Professor in Departments of Pharmacology and Psychiatry
Associate Director of OSU Program in Pharmacogenomics
5072C Graves Hall
333 W. 10th Avenue
Columbus, OH 43210
Phone: (614) 688-4573
Fax: (614) 292-7232
Email: saffen.1@osu.edu
Education
Yale University: BS in Molecular Biophysics and Biochemistry
Johns Hopkins: PhD in Biology (with Saul Roseman)
Johns Hopkins University, School of Medicine:
Postdoctoral Fellow in the Department of Molecular Biology and Genetics (with Daniel Nathans)
Johns Hopkins University, School of Medicine: Research Associate in the Department of Neuroscience (with Jay Baraban)
Research Interests
Neuropsychopharmacology, receptor mechanisms, signal transduction, regulation of intracellular protein kinases and calcium influx, inducible gene expression in the central nervous system, neuronal plasticity, Alzheimer's disease, the genetics and pharmacogenomics of schizophrenia, major depression and anxiety disorders.
Current ResearchMy lab is currently pursuing two lines of research. The first focuses on neuronal M1 muscarinic acetylcholine receptors, which function in attention, learning and memory, psychosis, and possibly, protection from Alzheimer's disease. Our goal is to elucidate intracellular signalling events that are regulated by M1 receptors, including calcium influx, activation of protein kinases and induction of gene expression. We anticipate that a clear understanding of downstream signaling pathways will lead to the identification of novel drug targets for the treatment of memory deficits in Alzheimer's disease and psychosis in schizophrenia and other mental disorders.
Our second line of research focuses on the identification of genes that contribute to mental illness, in particular schizophrenia, major depression and anxiety disorders. We hypothesize that genetic variants that alter the expression of key genes (i.e., producing too little or too much mRNA) contribute to the etiology of mental disorders. To test this hypothesis, we: 1) examine the candidate mental illness genes for allele-specific differences in mRNA expression, i.e., allelic expression imbalance (AEI); 2) search for single nucleotide polymorphisms (SNPs) located within or near each gene for allelic heterozygosity correlates with AEI; and 3) look for possible associations between high- or low-expressing alleles of these SNPs and mental illness. We recently demonstrated AEI for tryptophan hydroxylase 2 (TPH2) mRNA in human pons and identified high- and low-expressing alleles for several TPH2 SNPs. We will investigate whether low-expressing alleles for these SNPs associate with major depression or anxiety disorders. Our work on the genetics of mental illness is carried out in close collaboration with the laboratory of Wolfgang Sadee and the Core Lab of the OSU Program in Pharmacogenomics.
Techniques The techniques we use include: 1) analysis of intracellular kinase and gene expression in neurons and neuronal cells, 2) chromatin immunoprecipitation assay to identify the targets of transcription factor genes, 3) antisense RNA and siRNA, 4) single-cell imaging of calcium influx, 5) culture of neuronal cell lines, 6) genotyping using real-time PCR, primer-extension, and SNplex assays, 7) quantification of allele-specific mRNA expression in human brain, 8) most standard techniques of molecular biology.
Recent Publications
Lim JE, Pinsonneault J, Sadee W, Saffen D. Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNa expression in human pons. Molec Psych 12:491-501, 2007.
Ebihara, T., Guo, F., Zhang, L., Kim, J.Y. and Saffen, D. Muscarinic acetylcholine receptors stimulate Ca2+ influx in PC12D cells predominantly via activation of Ca2+ store-operated channels. J Biochem 139:449-458, 2006.
Zhang, I, Guo, F, Kim, J.Y. and Saffen, D. Muscarinic acetylcholine receptors activate TRPC6 channels in PC12D cells via Ca2+ store-independent mechanisms. J Biochem 139:459-470, 2006.
Lim, J.E., Papp, A., Pinsonneault, J., Sadee, W. and Saffen, D. Allelic expression of serotonin transporter (SERT) mRNA in human pons: lack of correlation with the polymorphism SERTPR. Molec Psych 11:649-662, 2006.
Kim, J.Y. and Saffen, D. Activation of M1 muscarinic acetylcholine receptors stimulates the formation of a multiprotein complex centered on TRPC6 channels. J Biol Chem 280:32035-32047, 2005.
Zhang, L. and Saffen, D. Muscarinic acetylcholine regulation of TRP6 Ca2+ channel isoforms: molecular structures and functional characterizations. J Biol Chem 276:13331-13339, 2001.
Guo, F.F., Kumahara, E. and Saffen, D. A CalDAG-GEFI/Rap1/B-Raf cassette couples M1 muscarinic acetylcholine receptors to the activation of ERK1/2. J Biol Chem 276:25568-25581, 2001.
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