Paul Albert, PhD

palbert@uottawa.ca
Telephone: 613-562-5800 ext. 8307
Fax: 613-562-5403

Senior Scientist, Ottawa Hospital Research Institute
Associate Director Neuroscience Program
CIHR/Novartis Michael Smith Chair in Neurosciences
Professor, Department of Medicine, Faculty of Medicine, University of Ottawa
Director, Neuroscience Graduate Program, University of Ottawa

Biographical Sketch

EDUCATION:

1975-77 D.E.C., Biology, Marianopolis College, Montreal, Quebec
1977-80 B.Sc., Honours, Physiology, major; Biochemistry, minor; McGill Univ., Montreal, Quebec
1980-85 Ph.D., Pharmacology, Harvard University, Boston, MA

RESEARCH EXPERIENCE:

9/81-9/85 Department of Pharmacology, Harvard, Thesis Director, Dr. A.H. Tashjian, Jr.
11/85-4/89 Post-doctoral Fellow, Vollum Institute of Advanced Biomedical Research, Portland OR. Directors, Dr. E. Herbert, Dr. O. Civelli.
4/89-6/94 Assistant Professor, Department of Pharmacology and Therapeutics, McGill.
6/94-12/95 Associate Professor, Department of Pharmacology and Therapeutics, McGill.
1/96-12/99 Adjunct Professor, Department of Pharmacology and Therapeutics, McGill.
12/95-5/00 Associate Professor, Department of Medicine, University of Ottawa.
1/96- CIHR/Novartis Michael Smith Chair in Neuroscience
1/98-5/01 Associate Member, Ottawa General Hospital Research Institute
5/2000- Full Professor, Departments of Medicine and Cellular and Molecular Medicine, University of Ottawa.
5/2001- Senior Scientist, Ottawa Hospital Research Institute
1/2005- Director, Neuroscience Graduate Program, University of Ottawa
9/2005- Associate Director, Ottawa Hospital Research Institute (Neuroscience)

Research

Professor Albert is working in the area of molecular mechanisms of autoreceptor desensitization. Successful therapy of major depression (as well as generalized anxiety, obsessive-compulsive, and other mental disorders) using a variety of antidepressant compounds (e.g., serotonin-specific reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, and 5-HT1A receptor agonists) is associated with a three-week time course before clinical improvement may be observed. Antidepressants appear to act by directly modifying the serotonergic system which originates in the raphe nuclei of the brain. Desensitization of inhibitory 5-HT1A autoreceptors occurs following chronic (but not acute) antidepressant treatment, and allows for enhanced firing of serotonergic raphe neurons in the presence of antidepressant. The enhanced firing results in increased serotonergic neurotransmission as the post-synaptic 5-HT receptors do not desensitize to the same extent. Receptor desensitization involves several sequential steps: uncoupling (min), mediated by phosphorylation, receptor sequestration (min-hr), and down-regulation (hr-days), involving receptor degradation and/or decreased receptor synthesis.

The importance of receptor phosphorylation, G proteins, and effectors in 5-HT1A and dopamine-D2 receptor signalling and desensitization is being probed in model cellular systems using a variety of molecular approaches, including: sense and antisense transfections, mutagenesis, cDNA cloning of novel receptors/kinases, immunoblotting/epitope tagging, and functional (cAMP, calcium, secretion) assays.

The importance of transcriptional and post-transcriptional events is being probed using 5-HT1A receptor promoter constructs, DNAase protection assays, RNAase protection assays, etc., with the ultimate aim of identifying genetic sequences that may confer susceptibility to mental disorders or responsiveness to anti-depressant treatment.

Professor Albert has established research collaborations with the Royal Ottawa Hospital (Institute for Mental Health Research) to apply this work in the areas of depression, anxiety and schizophrenia. He is also a member of the Heart and Stroke Foundation of Ontario Centre for Stroke Recovery (http://www.heartandstroke-centrestrokerecovery.ca/), a collaboration to identify genetic markers of recovery.

Research Topics:

1. 5-HT1A (serotonin) 1A receptor gene regulation

Hypothesis: Down-regulation of the 5-HT1A receptor gene mediates antidepressant actions of therapeutic compounds. Understanding the proteins that regulate the 5-HT1A promoter will lead to insights on receptor regulation relevant to depression, anxiety, obsessive compulsive disorder and other mental illnesses.
o Approaches: Cloning, sequence analysis, and characterization of repressors of the rat and human 5-HT1A receptor gene using luciferase reporter fusion constructs transfected in cell lines
o Identification of developmental regulation and co-repressors for 5-HT1A gene repressors
o Identification of other gene regulated by 5-HT1A gene repressors
o Studies of 5-HT1A receptor regulation in vivo using knockout mouse models.
o PCR analyses of patient samples for mutations in critical sites of 5-HT1A/DRD2 genes.
o Mechanisms of 5-HT1A gene regulation by 5-HT1A agonists and signaling pathways (e.g., calcium, cAMP, MAPK), glucocorticoids, estrogen.

2. 5-HT1A and dopamine D2 receptor signaling pathways

Hypothesis: Serotonin and dopamine receptors act through G proteins that couple to a diversity of intracellular signals to produce opposite (stimulatory vs. Inhibitory) responses depending on the cell type. We are characterizing the signaling/effector specificity of these receptors in fibroblast vs. pituitary cells to address the mechanisms involved.
o Approaches: Molecular characterization of G protein coupling specificity of 5-HT1A and dopamine D2S/D2L receptors in fibroblast vs. pituitary cell lines: development of stable antisense knockout approach.
o Molecular characterization of G protein coupling specificity using Galpha subunit mutants
o Role of specific G proteins in 5-HT1A and dopamine-D2 signaling by transfection of sense and antisense cDNA of specific G proteins and PTX- or RGS-insensitive G protein mutants.
o Interaction cloning of novel signaling proteins that interact with specific G proteins and their roles in D2-induced regulation of cell proliferation.
o Interaction studies of 5-HT1A protein domains involved in G protein activation
o 5-HT1A receptor signaling pathways in neurons

3. Mechanisms of desensitization of 5-HT1A and dopamine D2 receptors

.Hypothesis: The first steps in receptor desensitization (uncoupling) may play a key role in the longterm actions of the receptor, thus we are also examining mechanisms of acute receptor regulation by phosphorylation.
o Approaches: Molecular characterization of G protein-coupled receptor desensitization: pathway-selective desensitization by protein kinase C, mutagenesis studies of PK C substrate and pseudosubstrate sites in 5-HT1A and dopamine-D2 receptors.
o Development of phospho-specific anti-5-HT1A/D2 antibodies.
o Characterization of novel G protein-signaling pathways (eg. ceramide) and G protein desensitization by novel RGS proteins.

Selected Honours and Awards

1996 - CIHR/Novartis Michael Smith Chair in Neurosciences
1999 - First Annual Mentoring Award, Faculty of Medicine, University of Ottawa
2000 - John Dewan Prize, Ontario Mental Health Foundation

Selected Affiliations

1998-present - Organizing Committee, Great Lakes GPCR Retreat.
7/03-9/08 - Editorial Board, J. Biol. Chem.
12/03-present - - Editorial Board, Int. J. Neuropsychopharmacol
6/04-6/08 - Council Member, Canadian Congress of Neuropsychopharmacology
6/08-6/10 - Vice-President, Canadian Congress of Neuropsychopharmacology
3/05-3/08 - Member, Journals Managing Subcommittee, Endocrine Society

Current Funding

2007-2009: Regulation of Dopamine D2 Receptor Function, Ontario Mental Health Foundation
2005-2010: Transcriptional regulators of the 5-HT1A receptor gene, CIHR
2006-2011: Coupling domains of the 5-HT1A receptor, CIHR.

Key Selected Publications

1. Lemonde, S., Turecki, G., Bakish, D., Du, L., Hrdina, P. D., Bown, C.D., Basak, A., Kushwaha, N., Sequeira, A., Morris, S. J., Ou, X., and Albert, P.R. (2003). Impaired repression at a 5-hydroxytryptamine 1A receptor polymorphism associated with major depression and suicide. J. Neuroscience 23, 8788-8799.

2. *Ou, X.-M., *Lemonde, S., Jafar-Nejad, H., Bown, C.D., Goto, A., Rogaeva, A. and Albert, P.R. (2003) Freud-1: A neuronal calcium-regulated repressor of the 5-HT1A receptor gene. J. Neuroscience 23, 7415-25. *co-first authors

3. Lemonde, S., Du, L., Bakish, D., Hrdina, P. D., Albert, P.R. (2004) Association of the C(-1019)G 5-HT1A functional promoter polymorphism with antidepressant response. Int. J. Neuropsychopharmacol. 7, 501-506.

4. Kushwaha, N., Harwood, S.C., Wilson, A.M., Berger, M., Tecott, L.H., Roth, B.L. and Albert, P.R. (2006) Molecular determinants in the second intracellular loop of the 5-hydroxytryptamine(1A) (5-HT1A) receptor for G-protein coupling. Mol. Pharmacol. 69, 1518-26.

5. *Czesak, M., *Lemonde, S., Peterson, E.A., Rogaeva, A. Albert, P.R. (2006) Cell-specific repressor or enhancer activities of NUDR/Deaf-1 at a 5-HT1A receptor gene polymorphism. J. Neuroscience 26, 1864-71.

6. Morris, S.J., Itzhaki Van-Ham, I., Robillard, L., Sajedi, N., Daigle, M. and Albert, P.R. (2007) Differential desensitization of dopamine D(2) receptor isoforms by protein kinase C: The importance of receptor phosphorylation and pseudosubstrate sites. Eur J Pharmacol 577, 44-53.

7. Remes Lenicov, F., Lemonde, S., Czesak, M., Mosher, T.M., and Albert, P.R. (2007) Cell-type specific induction of tryptophan hydroxylase-2 gene transcription by calcium mobilization. J. Neurochem. 103, 2047-2057.

8. Rogaeva, A., Ou, X.-M., Jafar-Nejad, H., Lemonde, S., and Albert, P.R. (2007) Differential repression by Freud-1/CC2D1A at a polymorphic site in the dopamine-D2 receptor gene. J. Biol. Chem. 282, 20897-20905.

9. Jacobsen, K.X., Vanderluit, J., Slack, R.S., and Albert, P.R. (2008) HES1 regulates 5-HT1A receptor gene transcription at a functional polymorphism: Essential role in developmental expression. Mol. Cell. Neurosci. 38, 349-358.

10. Le François, B., Czesak, M., Steubl, D., Albert, P.R. (2008) Transcriptional regulation at a HTR1A polymorphism associated with mental illness. Neuropharmacol 55, 977-985.

11. Nafisi, H., Banihashemi, B., Daigle, M., Albert, P.R. (2008) GAP1(IP4BP)/RASA3 mediates Galpha(i)-induced inhibition of mitogen-activated protein kinase. J. Biol. Chem. 283, 35908-17

12. Hadjighassem, M.R., Szewczyk, B., Austin, M.C., Daigle, M., Stockmeier, C.A., Albert, P.R. (2009) Human Freud-2/CC2D1B: a novel repressor of post-synaptic 5-HT1A receptor expression. Biol. Psychiatry, in press.