|
|
 |
 |
 |
|
|
|
|
 |
Research Themes |
|
|
|
|
| |
 Peptide
mediators of inflammation : the kallikrein-kinin
system and the receptors for bradykinin-related
peptides
Ion
trapping of basic drugs into acidic cell compartments
: consequences for the safety and efficacy of
drugs from multiple therapeutic classes
Chronic
inflammatory processes at work in tumor biology
|
|
|
|
|
|
Research Projects |
|
|
|
|
| |
>>
CARDIOVASCULAR
PHARMACOLOGY OF THE B1 AND B2 RECEPTORS FOR KININS |
|
|
|
|
|
The kinins (bradykinin-related
peptides) are blood-derived mediators that act
on endothelial cells (producing endothelium-dependent
vasodilation, increased vascular permeability),
but also on smooth muscle cells, afferent sensory
neurons (inflammatory pain) and other tissues.
I have maintained a career-long interest in the
pharmacology of kinins, initially with studies
on the mechanism of the induction of the B1 receptor
subtype in immunopathology and, subsequently,
on the agonist-induced translocation/cycling of
both B1 and B2 receptors, the characterization
of novel ligands (now close to clinical evaluation)
and the relationship between receptors and other
critical physiopathological processes (interaction
with proteases/peptidases, the tissue factor-induced
initiation of coagulation and other reactions
relevant to sepsis and vascular biology).
This
project is supported by the Canadian Institutes
of Health Research (CIHR).
|
|
|
|
|
|
>>
ION TRAPPING AND
VACUOLIZATION : CONSEQUENCES FOR THE SAFETY AND
EFFICACY OF BASIC DRUGS |
|
|
|
|
| |
Many clinically used
drugs are basic amines (pKa 6 to 10) that are concentrated
in acidic cell compartments, especially the trans-Golgi
and other organelles that possess the V-ATPase.
The drugs, representing many different therapeutic
classes, remain trapped for prolonged periods. This
form of reservoir formation is generally counterproductive
as it alters the drug pharmacokinetics, distribution
and concentration at the sites of action. Further,
it is suspected that concentrated amines applied
locally or into confined anatomical areas will osmotically
attract water when sufficiently accumulated, producing
massive cell vacuolization, stress signaling and
inflammatory reactions (such as rhinitis medicamentosa,
the side effect of nasal decongestants applied to
the mucosa). The project aim to identify the cell
organelles affected by such trapping, its molecular
mechanisms and cellular consequences and to measure
its effect on the duration of action and dose-response
relationship for a model drug class, the adrenoceptor
agonists.
This
project is supported by the Canadian Institutes
of Health Research (CIHR).
|
|
|
|
|
|
>>
INFLAMMATORY GENES
AS VIRULENCE FACTORS IN TUMORIGENIC CELL LINES
|
|
|
|
|
| |
Several inflammatory
genes may act as progression factors in solid tumors,
at least in part because they promote angiogenesis:
tissue factor, the bradykinin B1 receptor, inducible
nitric oxide synthase (iNOS) and COX2. The following
questions will be pursued: What is the effect of
expressed transgenes selected from the list mentioned
above (tissue factor, kinin receptors) on the biology
of tumorigenic cell lines? (migration, MAP kinase
stimulation, cell growth, effect of ligands of these
surface proteins). What is the effect of these transgenes
on the tumors formed in the
chorioallantoic membrane?
(vascular density and configuration, tumor growth,
effect of drug co-administration).
This
project is supported by The Cancer Research Society,
Inc.
|
|
|
|
|
|
Selected references |
|
|
|
|
| |
Houle S., and Marceau
F. (2003) Wortmannin alters intracellular
trafficking of the bradykinin B2 receptor: role
of phosphatidylinositol-3 kinase and Rab5. Biochem.
J. 375: 151-158. PubMed
Link
Fortin J.P., Rivard
G.E., Adam A., and Marceau
F. (2005) Studies on rabbit natural and
recombinant tissue factors: intracellular retention
and regulation of surface expression in cultured
cells. Am. J. Physiol. Heart Circ. Physiol. 288:
H2192-2202. PubMed
Link
Fortin J.P., Dziadulewicz E.K., Gera L., and Marceau F. (2006) A nonpeptide antagonist reveals a highly glycosylated state of the rabbit kinin B 1 receptor. Mol. Pharmacol. 69: 1146-1157. PubMed Link
Morissette G., Petitclerc
E., and Marceau F. (2004) Loss of function of
vascular smooth muscle cells by nitric oxide-dependent
and -independent interactions with tumorigenic
cells. Int. J. Cancer 112 : 830-839. PubMed
Link
Morissette G., Moreau E., C.-Gaudreault R., and Marceau F. (2005) N -substituted 4-aminobenzamides (procainamide analogs) : an assessment of multiple cellular effects concerning ion trapping. Mol. Pharmacol. 68: 1576-1589. PubMed Link
|
|
|
|
|
 |
List of Publications - PubMed
Link
|
|
|
|
|
|
|
|
|
|
 |
Additional Information Details |
|
|
|
|
|
|
|
|
|
