Laboratory of Cellular and Molecular Pathophysiology: CAMH Research Annual Report 2002

Research in the Laboratory of Cellular and Molecular Pathophysiology Section investigates the cellular and molecular pathophysiology of the major psychoses, principally bipolar affective disorder, and the molecular pharmacology of antibipolar and antidepressant medications. The research team includes Dr. Jerry Warsh, clinician scientist, Dr. Peter Li, senior basic scientist, and their graduate student and postdoctoral trainees.Our groundbreaking, innovative research has led us to discover abnormalities in signalling processes inside nerve cells. These abnormalities play a critical role in the development of bipolar I disorder. A year ago, we identified patterns of changes, in several genes and their protein products, that affect intracellular calcium signalling in a subtype of bipolar I disorder. This year, we identified two novel target genes whose expression is regulated by lithium treatment; these genes may represent therapeutically relevant targets of this medication. Inositol monophosphatase type 2 is an enzyme found to be altered in cells from people who have bipolar disorder. Lithium, a mainstay in the treatment of bipolar disorder, blocks the activity of this family of enzymes. Using special gene-hunting techniques, our research team continues to identify genes that may be affected by lithium and other mood stabilizers. This year, we identified a gene that encodes diphosphoinositol polyphosphate phosphohydrolase, an enzyme that helps metabolize inositol polyphosphates. We identified another gene that encodes a transmembrane-4-superfamily protein, CD151. This is a scaffolding protein that interacts with several signalling molecules in the inositol lipid signalling pathway. These observations clearly support lithium's therapeutic potential to regulate the expression of a distinct set of genes involved in the signalling pathway(s) known to be dysregulated in bipolar disorder.Our findings of the past year continue the current goal of our research -- to translate our findings into clinical tests to more easily diagnose subtypes of bipolar disorder; and to predict which patients will respond to lithium or other mood-stabilizing medications. Our research grants, awarded by the Canadian Institute for Health Research and the Ontario Mental Health Foundation, now total $1,295,000. These grants allow our lab to conduct the studies necessary to produce clinical tests for use at the bedside and in the community. Our findings also set the stage to develop new drugs for treating and preventing relapses in bipolar disorder. The closer we come to understanding the specific chain of cellular disturbances that lead to this disorder, the more effectively we can work to develop new strategies to treat and prevent it.