Grant: Operating Grant

In transplanted organs, the vessels providing the blood supply to the organ become progressively narrowed due to rejection. This dramatically accelerates loss of function of the transplanted organ. Rejection increases the death rate of endothelial cells i.e. cells forming the inner lining of vessels within the transplanted organ. We have shown, with the support of the CIHR, that these damaged cells produce LG3, a novel mediator of importance in vascular repair and rejection. This mediator is produced by proteases released by dying cells that cleave the matrix surrounding the endothelial cells, therefore releasing LG3. We found that LG3 levels are increased in human renal transplant patients with rejection. Also, when injected in transplanted animals, LG3 increases the severity of vessel narrowing. In the present proposal, we plan to define the molecular pathways responsible for the production of LG3 by endothelial cells. We will also characterize the pathways activated by LG3 and leading to accelerated vessel narrowing. These experiments will provide insights into novel pathways of importance in rejection of transplanted organs in humans. A better understanding of these pathways will allow developing new strategies aimed at preventing rejection and prolonging the functional lifespan of transplanted organs.