Our laboratory has three research topics: the regulation of cell fate and homeostasis in response to stress, the mechanisms of HDL-mediated pancreatic beta cell protection, and the molecular characterization of tumor cell death induced by RasGAP-derived cell-permeable peptides.

1. In the first research topic, we study the role played by the caspase-3/p120 RasGAP stress sensor in the control of cell survival, NFkB regulation, and the modulation of cell metabolism. This sensor generates a RasGAP fragment, called fragment N, that activates Akt. This in turn stimulates survival pathways in cells and increases their metabolic activity. We are currently investigating the molecular mechanisms that mediate these two responses. In parallel we are studying the capacity of the caspase-3/RasGAP module to regulate cell metabolism and cell function in several in vitro and in vivo physiological situations. In particular, we are studying T cell responses, liver damage and skin wound healing as these are accompanied by changes in cell metabolism. This research is expected to provide important basic information on the homeostatic control of metabolism in stress conditions and in physiological conditions that lead to mild caspase-3 activation. Additionally, by providing a better understanding of the metabolic regulation during immune, wound healing, and repair responses, this project has the potential to contribute to refinement and improvement of immuno-therapies and procedures to facilitate tissue repair and regeneration.

2. HDL levels are inversely associated with diabetes development risks. They are known to efficiently protect beta cells against a variety of insults and this could contribute to their anti-diabetogenic properties. The molecular players mediating the protective functions of HDLs in beta cells are unknown however. We are performing unbiased screening assays to identify the molecules that are required for HDLs to inhibit beta cell apoptosis. Understanding the protective pathways activated by HDLs in beta cells is a pre-requisite for the development of drugs that stimulate or mimic the anti-diabetic effects of HDLs and thereby help to lower the risk, for example in overweight patients, to manifest type 2 diabetes mellitus.

3. We have identified a small peptide within the RasGAP protein that sensitizes tumor cell to various anti-cancer agents and that can even directly kill cancer cells in a few cases. Using CrispR/Cas9-based screening assays we are currently characterizing proteins that are mediating the anti-cancer activities of the RasGAP-derived peptide. These proteins are potential targets for the development of anti-cancer compounds.

Keywords

• Homeostasis
• cell metabolism
• stress responses
• signaling
• cancer