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Laboratory of Cellular
and Molecular Pathophysiology
Head: Dr. Jerry J. Warsh
Research in the Laboratory of Cellular and Molecular Pathophysiology
Section is devoted to investigating 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. Warsh, clinician scientist, Dr. Li, senior
basic scientist, and their graduate student and postdoctoral trainees.
Throughout the past decade, the team has done groundbreaking research
leading to the discovery of abnormalities, in several signalling processes
inside nerve cells, that play a critical role in the development of bipolar
I disorder. Using advanced molecular screening techniques, research by
the team culminated this year in reports on the identification of patterns
of changes, in several genes and their protein products, that affect intracellular
calcium signalling in a subtype of bipolar I disorder, a particularly
severe form of bipolar illness.
One gene product found to be altered is a protein that regulates the
entry of calcium into cells after pulses of calcium are released from
intracellular storage sites. Calcium has a very special role inside cells
as a signalling chemical. The processes that trigger calcium entry into
cells form the basis for producing signals that are carried through the
interior of cells in waves. The triggering of calcium entry by calcium
release from storage sites in cells is the biological equivalent of the
"capacitor" that is used in electronic devices to generate and
propagate signals. In people who have bipolar disorder and who also show
alterations in calcium signalling in their cells, we found a lower expression
of this protein. Of special importance, the gene for this capacitor protein
is located in a region on a chromosome that has been found in genetic
studies to be a potential "hot spot," as it contains a gene
that may increase the risk for developing bipolar disorder.
A second gene product found to be altered in cells from people who have
bipolar disorder is the enzyme inositol monophosphatase type 2. Lithium,
a mainstay in the treatment of bipolar disorder, is known to block the
activity of this family of enzymes. It has been suspected for some time
that this reduced activity may be important to the therapeutic effect
of lithium. The gene for inositol monophosphatase type 2 is located in
a region on chromosome 18 known as another gene hot spot that may also
increase the risk for developing bipolar disorder. This proximity is of
particular importance to tracking down what role the gene for inositol
monophosphatase type 2 plays in causing the illness.
Using special gene-hunting techniques, our research team also reported
identifying several genes that may be affected by lithium and some other
mood stabilizers. One of the genes produces the enzyme aldolase A. This
enzyme, which has several multiple functions, may also play a role in
regulating an important second messenger system that could influence a
number of critical processes in brain neurons, including cell growth and
cell death.
The findings, reported by our group during the past year, herald a new
phase in our research program -- translating these findings into potential
clinical tests to facilitate the diagnosis of subtypes of bipolar disorder;
and predicting those patients who will respond to lithium or other specific
mood-stabilizing medications. This task has been recognized in recent
research grants totalling $850,000, awarded by the Canadian Institute
for Health Research and the Ontario Mental Health Foundation, to conduct
the necessary studies to produce clinical tests for use at the bedside
and in the community. Our findings also set the stage for the development
of new drugs for treating and preventing relapses in this disorder. The
closer we come to understanding the specific chain of cellular disturbances
that lead to bipolar disorder, the more effectively we can work to develop
new strategies to treat and prevent it.
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