Grant: Operating Grant

In Canada, severe sepsis strikes young and old alike (~75,000 cases per year) and the mortality is 30-40%. Despite much research, no treatment for sepsis has emerged and the problem increases each year. Costs of ICU care for these patients are also enormous and post-acute care of survivors is nearly 3.5 million per year post-ICU discharge. New treatments are urgently needed. Treatment with Mesenchymal Stem Cell (MSCs) has been shown to reduce morbidity and mortality in septic animals. How these cells work is unclear so we analysed the expression of 54,000 genes in five sepsis-target organs collected from septic mice treated with either placebo or MSCs. We rationalized that genes important in helping mice get better and surviving would be changed between the sick mice and those that received the cells. We found that a particular gene usually involved in Parkinson disease (autosomal recessive, early onset) 7 [PARK-7] or DJ-1 was markedly changed in ALL 5 organs studied. We looked at the levels of the DJ-1 protein in patients with sepsis and found that not only was it increased, but it was significantly higher in those who died from sepsis. To determine the role of DJ-1 in sepsis, we obtained the mouse that lacked the DJ-1 gene and found that these mice were much more resistant to sepsis than the normal wild type mouse. The goal of the current grant application is to study the role of DJ-1 in the knockout mice and in different cells derived from these mice to better understand the mechanisms they have developed to protected themselves from sepsis. We think these mice are better able to cope with sepsis because absence of DJ-1 makes their immune cells much more aggressive getting rid of bacteria. Moreover, we also study the option of inhibiting DJ-1 in MSCs or conditioned medium from cells - to determine if this approach can be used to improve the beneficial effects of MSC treatment or even serve as an approach in itself for the treatment of sepsis.