Research
Kidney Fibrosis
Kidney disease currently affects 1 in every 10 Canadians, costing our Canadian healthcare system $2.5 billion/yr for 0.06% of Canadians on dialysis and $40 billion in the broad management of the disease. Fibrosis is a maladaptive repair response common to the development of an assortment of chronic kidney diseases (CKDs) and cancers. It is characterized by aberrantly excessive deposition and processing of extracellular matrix (ECM) materials, like collagen and fibronectin. Accumulation of ECM proteins can shift a constructive restoration towards a destructive remodeling (stiffening) of the tissue, which progressively leads to organ malfunction and, ultimately, death.
A fundamental unanswered question in the pathogenesis of fibrosis is the molecular mechanism that determines the switch from a controlled to an aberrant ECM remodeling response during chronic injury and cancer. In this context, inhibiting factors that regulate ECM expression and processing represents a logical therapeutic approachIn order to study such fascinating proteins, our lab uses a variety of established in vitro and in vivo models so as to translate findings for human extrapolation. Our approach includes a variety of cell types, mouse models of kidney injury/carcinomas and human biopsies (plasma, urine and tissue), which are analyzed using various wide-screening (RNA-seq, MS/MS), molecular (siRNA/DNA transfections, immunoassays, immunoprecipitations) and cellular (fluorescent/optical microscopy) methods.
Matrix Biology
Important to ECM processing and regulation of cell-ECM interactions are the under-recognized matricellular proteins (MCPs).
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Our objective is to investigate how the induction of MCPs regulates initiation and progression of kidney repair/tumorigenesis and whether genetic or pharmacologic modulation of such proteins are capable of altering the ultimate outcome of kidney fibrosis/cancer. Specifically, the aims of our lab are:
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To determine which MCP expression levels have in vivo relevance between basal, fibrotic and tumorigenic conditions.
To analyze the role MCPs play on cell-ECM interactions using kidney fibroblasts, tubular epithelial cells and renal cell carcinoma (RCC) cell lines.
To investigate the therapeutic implications of targeting MCPs and their downstream pathways.
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Considering that MCPs are specific to regulating the ECM composition during tissue remodeling processes, i.e. fibrosis and cancer, our research is expected to have a significant impact because it will provide an important rationale to target MCPs during fibrosis/tumorigenesis so as to minimize the side-effects typically observed with pleotropic targets.
Pediatric Leukemia
The normal cells of our body continuously grow and multiply in a controlled manner for the proper maintenance of our tissue and organs. However, these same events are uncontrolled during leukemia and lead to a large number of cells (tumor) which end normal organ function. A gene that is important in regulating such events is p53. Also known as a tumor blocking gene, p53 signals a reduction in cell numbers when they unusually reach harmful levels, in order to prevent further tumor formation. p53 signalling is a very powerful process as evidenced by 2 main facts: i) a functional p53 is extremely helpful for a cell to respond to key cancer therapies, such as chemo- and radio-therapy ii) many cancers experience a blockage in p53 function, including children with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Moreover, leukemia patients do not respond to chemo- and radio-therapy probably due to their malfunctioning p53. Therefore, a better understanding of the procedures regulating the function of p53 will not only offer new awareness into cancer development but also allow the development of strategies to restore p53 function necessary for cancer treatments.