> Review articles
||MOLECULAR AND BIOCHEMICAL BASIS OF LYSOSOMAL
STORAGE DISORDERS. My laboratory made a substantial
contribution in the discovery of genes mutated in lysosomal
storage diseases, hereditary conditions of children previously
considered to be untreatable. We were the first to clone the
gene for sialidase Neu1 which deficiency causes severe storage
disease, sialidosis and to define the mechanisms causing sialidosis
in patients. We characterized the lysosomal multienzyme complex
containing sialidase, galactosidase, galacto-6-sulfatase and
cathepsin A, deficient in GM1-galactosidosis, galactosialidosis
and Morquio disease. Our studies explained the pathogenic
mechanism of these genetic diseases, provided methods for
their molecular diagnostics and revealed data that changed
the view on the organization and functioning of lysosomal
matrix enzymes. Most recently we have mapped the chromosomal
position of the gene defective in another lysosomal disease,
Mucopolysaccharidosis III C.
||BIOGENESIS OF LYSOSOMAL ENZYMES. We
identified structurally conserved surface regions in several
lysosomal cathepsins and showed that they represent phosphotransferase
recognition sites important for internalization and trafficking
of these enzymes. The lysosomal sialidase, Neu1 was targeted
to the lysosome through different mechanism, adapter protein-mediated
vesicular pathway. We further demonstrated that in the immune
cells i.e. activated T lymphocytes or differentiating monocytes
Neu1 is directed to the cell surface, which may be potentially
important for immune function.
||PROTEOMICS AND FUNCTIONAL GENOMICS OF
THE LYSOSOME. We have defined the proteomes of the
lysosomal membrane and matrix, as a part of global Cell Map
established by the Montreal Proteomics Network. The goal of
this project funded by Genome Quebec is to identify the resident
and associated proteins of all organelles and molecular machines
of the eukaryotic cell by large-scale proteomics. These studies
have defined a new lysosomal sialidase Neu4, important for
developing new therapies for sialidosis and galactosialidosis.
In complementary studies, using RNA arrays, we have identified
genes, whose expression is induced or silenced in the cells
of patients affected with lysosomal storage and defined that
impairment of the ubiquitin-dependent protein degradation
pathway represents a common pathogenic mechanism.
||COMPARATIVE PROTEOMICS OF HUMAN DISEASES.
I am a director of the Sainte-Justine Hospital Proteomics
Laboratory, which was established using my Canadian Foundation
for Innovation grant. We use proteomics-based technology for
diagnostics and for discovery of targets for treatment and
prevention of human diseases. We collaborate with researchers
from gastroenterology (proteomics of disorders of the bile
ducts), genetics (proteomics of the fat cell implicated in
paediatric obesity), medicine (proteomics of the blood vessel
wall in hypertension), and paediatric oncology (proteomics
of leukaemia cells). In the project funded by Genome Quebec/Genome
Canada we use proteomics to identify candidate genes for susceptibility
to T2 Diabetes Mellitus. Our studies of proteomes of blood
vessel cells helped to establish new signalling pathways for
arterial vasculature whereas functional proteomic study of
the fat tissue defined a new major adipocyte lipase.
||DEVELOPMENT OF NEW PROTEOMIC TECHNOLOGY.
We have developed a new technology for quantification of proteins
in a proteome. This method based on peptide labelling with
stable isotopes provides effective and accurate quantification
of proteins and is also useful for the analysis of their post-translational
modifications, as well as for the study of protein-protein
||CLINICAL RESEARCH. For almost 4 years I
am a Scientific Supervisor of the Medical Genetics Diagnostic
Laboratory at Ste-Justine Hospital that performs analyses
on patients with inherited lysosomal and metabolic disorders.
Together with the personal of the laboratory we develop new
biochemical and enzymatic tests.