Grant: Project Grant

Finding new therapies for rare diseases is an urgent need in Canada. Our research program seeks to develop effective and safe treatments for patients with lymphangioleiomyomatosis (LAM), a devastating lung disease that causes destruction and failure of the lungs. LAM is caused by cancer-like abnormalities arising in cells (LAM cells) with genetic mutations in the 'tuberous sclerosis complex-2' (TSC2) gene. LAM also develops in ~1/3 of patients with 'tuberous sclerosis complex' (TSC), an inherited disease of mutations in the TSC1 or TSC2 gene that affect ~1 in 6000 Canadians, and leads to tumours in multiple body locations. Key roadblocks in finding new treatments for LAM include the inability to grow and study LAM cells from patients, and a poor understanding of how loss of TSC2 gene function contribute to their cancer-like properties. In pilot studies, we identified the hormone 'urotensin' as a potential target for therapy that is particularly active in LAM cells. At the same time, we used stem cell technology to engineer a 'test tube' model that closely resembles LAM cells from patients, and that can be used to discover potential therapies. In Part 1 of this project, we will to use these LAM-like cells to understand the cellular mechanism(s) by which urotensin activity is altered in LAM cells, and how urotensin contributes to their cancer-like properties. In Aim 2, we will use LAM-like cells in state-of-the-art drug screening protocols to identify drug regimens that are less toxic and more effective than current therapies for LAM.