Dalhousie University Dalhousie University Faculty of Medicine Department of Pharmacology
   
 



Faculty

Eileen M Denovan-Wright, PhD

Professor

BSc Hon (Dalhousie), PhD (Dalhousie)

Keywords

Molecular biology, gene expression, brain, Huntington's disease, quantitative PCR, transcription, gene therapy, molecular neuropharmacology, cannabinoids, cannabinoid receptor

Current Research

Huntington's disease results from the inheritance of a mutated copy of the huntingtin gene. The abnormal huntingtin protein, like the normal copy, is expressed throughout the human brain and body but only cells in a very specific region of the brain die after several decades of life. Huntington's disease patients have emotional and psychiatric symptoms before cell death suggesting that brain function is affected early in the development of this disease. Several transgenic mouse models of Huntington's disease are available. We have been investigating how the brains of transgenic Huntington's disease mice differ from normal mice. We have identified time-dependent and cell-specific decreases in the levels of the messages of several genes. These decreases occur before mice develop the symptoms of Huntington's disease. Our goal is to determine how mutant huntingtin causes mRNA level to decrease. It is hoped that a description of the genes affected early in the development of Huntington's disease and an understanding of the mechanism that leads to decreases in the levels of the messages for these genes will point to therapeutic strategies to lessen the symptoms or slow the disease. Levels of the type 1 cannabinoid receptor (CB1) are lower in HD brain tissue from humans and mouse models and in cells expressing mutant huntingtin. Although levels and distribution of CB1 are similar in very young HD mice compared to wild-types, CB1 levels decline relatively early in young adult HD mice. CB1 receptor function in the brain modulates presynaptic neurotransmitter release and is linked to cell viability. We are studying the regulation of the CB1 receptor and whether manipulation of the endogenous cannabinoid system or delivery of exogenous cannabinoids alters progression of Huntingtons disease.

Membership in professional societies

Society for Neuroscience

Canadian Society for Biochemistry, Molecular and Cellular Biology.

Canadian College of Neuropsychopharmacology

Canadian Association for Neuroscience

Graduate Students and Postdoctoral Fellows supervised (2006-2012)

Sophie Rowlands (PDF, Reynold Fellowship Department of Pharmacology, 2012-2013)

Robert Laprairie (Ph.D. Pharmacology, 2012-2016)

Amina Bagher (Ph.D. Pharmacology - co-supervised with Dr. M.E. Kelly)

Robert Laprairie (M.Sc. Pharmacology/Neuroscience, 2010-2012)

Greg Hosier (M.Sc. Pharmacology/Neuroscience, 2010-2012)

Amina Bagher (M.Sc. Pharmacology - co-supervised with Dr. M.E. Kelly)

Carmelia Giampa (PDF, 2008)

Fernanda Alves-Costa (PDF, 2008)

Matthew Hogel (Ph.D. Pharmacology/Neuroscience, 2006-2011)

Geraldine Gomez (Ph.D. Pharmacology/Neuroscience, 2002-2006)

Haibei Hu (Ph.D. Pharmacology/Neuroscience, 2003-2007)

Selected Publications

(2006-2012)

Laprairie, R.B., Kelly, M.E.M., and Denovan-Wright, E.M. (2012). The highs and lows of CB1 transcription (2012-BJP-0343-RCT) British Journal of Pharmacology, In press, July 2012.

Hogel, M., Laprairie, R.B., and Denovan-Wright, E.M. (2012). Promoters are differentially sensitive to N-terminal mutant huntingtin-mediated transcriptional repression. Public Library of Science One, 7(7): e41152.

Venkatachalam, A., Lall, S.P., Denovan-Wright, E.M. and Wright, J.M. (2012) Tissue-specific differential induction of duplicated fatty acid-binding protein genes by the peroxisome proliferator, clofibrate, in zebrafish (Danio rerio). BMC Evolutionary Biology, Accepted May 28, 2012.

Denovan-Wright, E.M. and Currie, R.W. (2011) Silence of the limbs (an invited editorial of siRNA knock-down in ischemic tissue). Circulation Research. 92:85-86.

Tebbenkamp, A.T.N., Green, C., Xu, G., Denovan-Wright, E.M., Rising, A.C., Fromholt, S.E., Brown, H.S., Swing, D., Mandel, R.J., Tessarollo, L., Borchelt, D.R. (2011) Profound dyskinesia and cerebellar degeneration in transgenic mice expressing a caspase-6 derived fragment of mutant huntingtin. Human Molecular Genetics 20:2770-2782.

Rising, A.C., Xu, J., Napoli, V.V., Carlson, A., Denovan-Wright, E.M. and Mandel, R. (2011) Longitudinal Behavioral, Cross-sectional, Transcriptional and Histopathological Characterization of a Knock-In Mouse Model of Huntingtons Disease with 140 CAG Repeats. Experimental Neurology. 228:173-182.

Gauthier C., Fenwick N., Denovan-Wright E.M., and Griffin G. (2011). Enhancing effective Three Rs searches the CCAC Three Rs search guide. Proceedings of the Eleventh FELASA Symposium and the 40th Scand-LAS symposium, 14-17 June 2010, Helsinki, Finland: 11-17. http://www.felasa.eu/media/uploads/Proceedings_FELASA-ScandLAS-2010_small_SEC.pdf

Karanth, S., Denovan-Wright, E.M., Thisse, C., Thisse, B. and Wright, J.M. (2009) Tandem duplication of the fabp1b gene and subsequent divergence of the tissue-specific distribution of fabp1b.1 and fabp1b.2 transcripts in zebrafish (Danio rerio). Genome. 52:985-992.

Karanth, S., Lall, S.P., Denovan-Wright, E.M. and Wright, J.M. (2009) Differential transcriptional modulation of duplicated fatty acid-binding protein genes by dietary fatty acids in zebrafish (Danio rerio): evidence for subfunctionalization and neofunctionalization of duplicated genes. Biomed Central. 9:219.

Denovan-Wright, E.M., Attis, M., Rodriguez-Lebron, E., and Mandel, R.J. (2008) Sustained striatal CNTF expression negatively affects behavior and gene expression in normal and R6/1 mice. Journal of Neuroscience Research 86:1748-1757.

Denovan-Wright, E.M., Rodriguez-Lebron, E., Lewin, A.S. and Mandel, R. (2008) Unexpected off-targeting effects of anti-huntingtin ribozymes and siRNA in vivo. Neurobiology of Disease. 29:446-455.

Hebb, A.L.O, Robertson, H.A. and Denovan-Wright, E.M. (2008) Phosphodiesterase 10A inhibition is associated with locomotor and cognitive deficits and increased anxiety in mice. European Neuropsychopharmacology 18:339-363.

Karantha, S, Denovan-Wright, E.M., Thisse, C., Thisse, B. and Wright, J.M. (2008) The evolutionary relationship between the duplicated copies of the zebrafish fabp11 gene and the tetrapod FABP4, FABP5, FABP8 and FABP9 genes. FEBS Journal 275:3031-3045.

Alves, F., Denovan-Wright, E.M., Thisse, C., Thisse, B. and Wright, J.M. (2008) Spatio-temporal distribution of fatty acid-binding protein 6 (fabp6) gene transcripts in the developing and adult zebrafish (Danio rerio). FEBS Journal, 275:3325-3334.

Liu, R-Z, Saxena, V., Sharma, M.K., Thisse, C., Thisse, B., Denovan-Wright, E.M. and Wright, J.M. (2007) The fabp4 gene of zebrafish (Danio rerio): genomic homology with the mammalian FABP4 and divergence from the zebrafish fabp3 in developmental expression. FEBS Journal 274:1621-1633.

Roy, J., Denovan-Wright, E.M., Linsdell, P. and Cowley, E.A. (2006) Exposure to Sodium Butyrate Leads to Functional Down-Regulation of Calcium-Activated Potassium Channels in Human Airway Epithelial Cells. Plfugers Archive-European Journal of Physiology 453:167-176.

Sharma, M.K., Liu, R-Z., Thisse, C., Thisse, B., Denovan-Wright, E.M. and Wright, J.M. (2006) Hierarchiacal subfunctionalization of fabp1a, fabp1b and fabp10 tissue-specific expression my account for retention of these duplicated genes in the zebrafish (Danio rerio) genome. FEBS Journal 273:3216-3229.

Gomez, G.T., Hu, H., McCaw, E.A. and Denovan-Wright, E.M. (2006) Mutant huntingtin-induced transcriptional dysregulation of the DARPP-32 gene is dependent on striatal proteins. Molecular Cellular Neuroscience 31:661-675.

Denovan-Wright, E.M. and Davidson, B.L. (2006) RNAi: A potential therapy for the dominantly inherited nucleotide repeat diseases. Gene Therapy 13:525-531.

BOOK CHAPTERS:

Laprairie RB, Hosier G, Hogel M, and Denovan-Wright EM (2011). Alterations in expression and function of phosphodiesterases in Huntingtons disease. Huntingtons disease. InTech Open Access Publishing ISBN 979-953-307-066-6. Ed. Nagehan Ersoy Tunali. Ch. 6 pp. 133  172. (Book Chapter).

Contact Information

Department of Pharmacology
Room 6E, 6th Floor
Sir Charles Tupper Medical Building
Dalhousie University
5850 College Street
PO Box 15000
Halifax, Nova Scotia
Canada B3H 4R2

Phone: 494-1363

Fax: 494-6294

Email: emdenova@dal.ca