Kristine Wiren
Research Biologist, Research Service, VAMC
Associate Professor, Behavioral Neuroscience, OHSU
Associate Professor, Department of Medicine, OHSU
e-mail: wirenk@ohsu.edu
Major Areas
Molecular mechanisms mediating withdrawal; neuroendocrinology; steroid receptor regulation
Previous Positions
Post-doctoral Fellow, Harvard Medical School and the Massachusetts General Hospital
Research Molecular Biologist, American Lake VAMC, Tacoma
Research Associate, Department of Medicine, University of Washington
Education
B.A. (1974) Oregon State University
Ph.D. (1985) University of Connecticut Health Center
Research Interests
The development of alcoholism is complex, progressive and is influenced by multiple genes. Long-term ethanol use can produce tolerance and physical dependence, typically shown by the appearance of a withdrawal syndrome after discontinued use of alcohol. When alcohol is used repeatedly, changes in brain gene expression and in neural networks occur, collectively termed neuroadaptation. Importantly, neuroadaptation likely contributes to withdrawal-induced central nervous system hyperexcitability and potentially neurotoxicity. The development of alcoholism shows gender specificity, with females at reduced risk for becoming alcoholic but developing more severe organ damage than males. The Wiren laboratory is using a multidisciplinary molecular approach to identify genes of importance in the development of neuroadaptation in both sexes, to identify changes in expression that occur after withdrawal and those that persist during protracted periods of abstinence after chronic exposure. To achieve this, both male and female selected replicate lines of mice with highly divergent withdrawal severity are exposed to chronic ethanol and allowed to recover for varying lengths of time, including an extended period of abstinence. Discrete brain regions are examined using gene chip analyses to establish a time-course for gene expression changes in specific brain circuits. Using this approach, my laboratory is characterizing molecular mechanisms underlying neuroadaptation to ethanol, including those that may reflect the influence of the steroid hormones estrogen and/or androgen. By employing bioinformatic analyses, underlying signaling pathways are characterized to identify gene networks that may be of importance in mediating the development of alcoholism in both sexes. One example of this approach is the discovery of female vulnerability for brain damage after withdrawal from chronic ethanol exposure. In addition, since persistent changes of gene expression in abstinent alcoholics are thought to influence risk to relapse, perhaps for a lifetime, we are also characterizing genes that may contribute to such risk. The ultimate aim is to test the functional/regulatory significance of genes of interest in transgenic models or by antisense intervention. Collectively these studies should increase our understanding of the mechanisms involved in the development of alcohol dependence, and may help identify at-risk individuals for targeted intervention. These studies could provide for more effective treatments for alcoholism, in both males and females, including treatments that may reduce the risk of relapse in abstinent alcoholics.
Selected Recent Publications
Hashimoto J, Wiren KM: Neurotoxic consequences of chronic alcohol withdrawal: expression profiling reveals importance of gender over withdrawal severity. In review, 2006
Wiren KM, Hashimoto JG, Alele PE , Devaud LL, Price KL, Middaugh LD, Grant KA, Finn DA: Impact of sex: Determination of alcohol neuroadaptation and reinforcement. Alcohol Clin Exp Res 30(2):233-42, 2006
Beadles-Bohling A, Wiren KM: Anticonvulsive effects of kappa opioid receptor modulation in an animal model of ethanol withdrawal. Genes Brain Behav 5: 483–496, 2006
Finn DA, Beadles-Bohling A, Beckley E, Ford M, Gililland K, Gorin-Meyer R, Wiren KM: A new look at the 5 a -reductase inhibitor finasteride. CNS Drug Rev 12(1):53-76, 2006
McBride WJ, Kerns RT, Rodd ZA, Strother WN, Edenberg HJ, Hashimoto JG, Wiren KM, Miles MF: Alcohol effects on central nervous system gene expression in genetic animal models. Alcohol Clin Exp Res 29(2):167-175, 2005
Beadles-Bohling A, Wiren KM: Altered kappa opioid receptor system expression in distinct brain regions of a genetic model of enhanced ethanol withdrawal severity. Brain Res 1046(1-2):77-89, 2005
Hashimoto JG, Beadles-Bohling AS , Wiren KM: Comparison of RiboGreen and 18S rRNA quantitation for normalizing real-time RT-PCR expression analysis. Biotechniques 36(1):54-6, 58-60, 2004
Finn DA, Ford MM, Wiren KM, Roselli CE, Crabbe JC. The role of pregnane neurosteroids in ethanol withdrawal: behavioral genetic approaches. Pharmacol Ther 101(2):91-112, 2004
Crabbe JC, Wiren KM: Molecular and Genetic Bases of the Addictions. In: The Molecular and Genetic Basis of Neurologic and Psychiatric Disease, (R Rosenberg , S Prusiner, S DiMauro, R Barchi and E Nestler, Eds), Butterworth-Heinemann Medical Publishing, Woburn , MA , pp. 779-789, 2003