Faculty Biosketch                           Milton S. Hershey Medical Center
                                                                       Penn State College of Medicine
                                                                       P.O. Box 850, 
                                                                       500 University Drive
                                                                       Hershey, PA 17033-2390

Kent E. Vrana, Ph.D. Elliot S. Vesell Professor and Chair of Pharmacology	Office Information                  Phone: 717-531-8285  Mail Code: H078 E-Mail: kvrana@psu.edu
Education
B.S., University of Iowa, 1978 Ph.D., Louisiana State University, 1983 Post Doc Fellowship, NIH Postdoctoral Fellow, DB Brown, 83-86, Carnegie Institution of Washington, Dept. Embryology, Baltimore, MD

The rate-limiting enzyme in catecholamine biosynthesis is tyrosine hydroxylase (TH), while the rate-limiting enzyme in serotonin biosynthesis is tryptophan hydroxylase (TPH). In one aspect of our work, full-length cDNA clones for TH and TPH are modified by site-directed mutagenesis and the mutant proteins expressed in bacteria.  The recombinant enzymes are then characterized in terms of their structure., activity and regulation. The results of these studies provide insights into how these pivotal enzymes function in health and disease.  A central premise of our second research are is that chronic drug abuse creates an epigenetic imprint - a stable environmental alteration in the pattern of gene expression - that contributes to such clinical observations as physical dependence, psychological addition, withdrawal and relapse liability. Moreover, some individuals can inherit such a pattern of gene expression creating an increased risk of abuse liability. While this laboratory has characterized environmental effects on gene expression for many years, we have more recently adopted high throughout methods (multiplex DNA arrays and SELDI/MALDI-TOF mass spectrometry) to identify those mRNAs and proteins that are engaged in the polygenic problem of substance abuse.  In a third aspect of our work, molecular tools have been brought bear on a number of problems related to neurodegenerative disease.  These have included: genotyping genetic factors related to Alzheimer's Disease (ApoE and presenilin); investigating the role of dopamine quinone production and covalent modification in dopamine-mediated neurotoxicity (Parkinson's Disease); and examining the environmental neurotoxicology associated with manganese exposure.  Recent efforts are also examining the genetics of metal metabolism as it may relate to autism.

New efforts within the laboratory include application of cloning technologies to non-human primates. We have recently been involved in a collaborative effort that has demonstrated the ability to generate pluripotent embryonic stem cells via parthenogenetic activation of oocytes.  This ability to create ES cells from non-fertilized, self-limiting, and non-viable embryos may provide ethical alternatives to the use of fertilized embryos in therapeutic cloning application.  Proteomic and functional genomic tools are being used to profile those genes and gene products that contribute to "stemness", as well as stem cell differentiation (both non-human primate and human embryonic stem cells). Finally, the laboratory is also interested in developing new publication paradigms that utilize the power of the Internet to create highly interactive bibliographic databases.  These e-reviews have the potential to become long-term, dynamic and up-to-date sources of information for the scientific community.

1. Cibelli JB, Grant KA, Chapman KB, Cunniff K, Worst T, Green HL, Walker SJ, Gutin PH, Vilner L, Tabar V, Dominko T, Kane J, Wettstein PJ, Lanza RP, Studer L, Vrana KE, West MD. Parthenogenetic stem cells in non human primates. Science 2002; 295-819.
2. Freeman WM, Brebner K, Patel KM, Lynch WJ, Roberts DCS, Vrana KE. Repeated cocaine self-administration causes multiple changes in rat frontal cortex gene expression. Neurochem Res 2002; 27:1181-1192.
3. Stokes AH, Freeman WM, Mitchell SG, Burnette TA, Hellman GE, Vrana KE.  Induction of GADD45 and GADD153 in neuroblastoma cells by dopamine-induced toxicity. NeuroToxicology 2002; 23:675-684.
4. Patel VB, Chaurand P, Caprioli RM, Austen BM, Freers ER, Manca F, Davies H, Vrana KE, Wheeler M, Preedy VR. Emerging techniques in biomedical research and their application to alcohol toxicity. Alcohol Clin Exp Res 2003;27:348-353.
5. Worst TJ, Freeman WM, Walker SJ, Vrana KE. Systematic screening of gene expression using a cDNA macroarray. Meth Mol Med 2003; 79-243-259.
6. Walker SJ, Worst TJ, Vrana KE. Semi-quantitative real-time PCR for analysis of mRNA levels. Meth Mol Med 2003; 79-211-227.
7. Vrana KE, Freeman WM, Aschner M. Use of microarray technologies in toxicology research. NeuroToxicology 2003;24:321-332.
8. Vrana KE, Hipp JD, Goss AM, McCool B, Riddle D, Walker SJ, Wettstein P, West MD, Grant KA, Cibella JB. Non-human primate parthenogenetic stem cells. Proc Natl Acad Sci USA 2003; 100:11911-11916.
9. Yohrling IV GJ, Jiang GC-T, DeJohn MM, Miller DW, Young AB, Vrana KE, Cha JH-J. Analysis of cellular transgenic and human models of Huntington's disease reveals tyrosine hydroxylase alterations and substantia nigra neuropathology. Mol Brain Res 2003; 119:28-36.
10. Kasinathan C, Vrana K, Beretta L, Thomas P, Gooch R, Worst T, Walker S, Xu A, Pierre P, Green H, Grant K, Manowitz P. The future of proteomics in the study of alcoholism. Alcohol Clin Exp Res 2004; 28(2):228-232.
11. Walker SJ, Worst, TJ, Freeman WM, Vrana KE. Functional genomic analysis in pain research using using hybridization arrays. Methods Mol Med 2004; 99:239-253.
12. Stredrick DL, Stokes AH, Worst TJ, Freeman WM, Johnson EA, Lash LH, Ascher M, Vrana KE. Manganese-induced cytotoxicity in dopamine-producing cells. Neurotoxicology 2004;25(4):543-553.
13. Worst TJ, Vrana KE. Alcohol and gene expression in the central nervous system. Alcohol Alcohol 2005; 40(1):63-75.
14. McCracken CB, Patel KM, Vrana KE, Paul DL, Roberts DCS. Amphetamine withdrawal produces region-specific and time-dependent changes in connexin36 expression in rat. Synapse, 2005; accepted, pending revision.

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