Luc Sabourin, PhD lsabourin@ohri.ca General Campus (see Contact page for maps)

Senior Scientist, Cancer Therapeutics, Ottawa Hospital Research Institute

1. Plasticity and Cellular Remodeling Cell survival, movement, differentiation and growth is dependent on interactions between cell surface proteins called integrins and components of the extracellular matrix. These interactions trigger the clustering of several signaling molecules on the cytoplasmic side of the cells at sites of adhesions. These activated signaling complexes then modulate the activity of various kinases and other signal transducers implicated in the control of cell shape, survival and proliferation. A number of processes such as growth cone progression, axonal guidance and tumor invasion are highly dependent on the activity of these signaling molecules.

   Professor Sabourin's laboratory has recently cloned a novel Ste20-related kinase involved in apoptosis and cytoskeletal remodeling. Overexpression of this novel kinase, termed SMAK, in a variety of cell types, induces cell death and disassembly of actin stress fibers and focal contacts. Using biochemical approaches and cell culture systems, they are currently focusing on the remodeling events and signaling pathways that are modulated by SMAK and the upstream signals that regulate its activity. Applying yeast two hybrid and in situ protein-protein interaction screens, they are attempting to isolate SMAK binding proteins and substrates. In addition, gene knock-out and transgenic technology is currently being used in the laboratory to investigate the role of SMAK during embryonic development. They have already identified several oncogenes that regulate the activity of SMAK, suggesting a role for SMAK in tumorigenesis and invasiveness. Defining the pathways that regulate apoptosis and cellular remodeling will prove useful in the design of treatment against highly metastatic tumors and post-traumatic injuries such as ischemia.

2. Myotonic Dystrophy Myotonic Dystrophy (DM) is an autosomal dominant heritable disorder that affects 1 in 8000 individuals globally. DM is caused by the expansion of a polymorphic (CTG)n repeat found in the 3' untranslated region of a serine/threonine protein kinase (DMPK). The adult onset of DM is characterized mainly by myotonia, progressive muscle wasting and cardiac conduction defects. Severe congenital cases display hypotonia, developmental defects and mental retardation. The mechanisms by which the CTG repeat expansion mediates the DM phenotype is still elusive and the normal function of the DMPK protein is still unknown. In addition, to date, there are no animal models allowing the investigation of the mechanisms underlying the pathogenesis of DM in vivo.

   Professor Sabourin's laboratory focuses on the biochemical characterization of DMPK using cell culture and transgenic approaches. They are investigating the signaling pathways that regulate DMPK activity as well as the characterization of DMPK signal effector proteins. In addition, they have initiated the generation of transgenic animal models for DM using the Cre-loxP recombination technology. This novel approach will allow the production of animals that can be induced to express the DM mutation in a time-dependent and tissue-specific manner. This system will allow the investigation of the mechanisms underlying DM in vivo and in vitro using primary cultures derived from DM animals. The establishment of a DM animal model will provide a system in which potential therapies can be tested and evaluated.