Grant: Operating Grant - PA: ICRH - New investigators (Bridge Funding)

In Canada, severe sepsis strikes young and old alike with an incidence of ~75,000 cases per year, a mortality of 30-40%. Given the rising numbers (8.7%/yr), by 2026 about 34,000 Ontarians are expected to be in the intensive care unit (ICU) on life support, many with severe sepsis complicated by new organ failure. Currently, no specific treatment exists. Patients are treated with antibiotics and supportive care. Accordingly, there is an unmet and urgent need for novel treatments.Recently, we have shown that treatment with Mesenchymal Stromal/Stem Cells (MSCs) can improve inflammation and mortality in septic mice. But how these cells actually work is unclear. To determine this, we used gene-chip and bioinformatics to identify changes in the expression of genes (and their regulators) associated with survival in septic mice that received MSCs rather than placebo. We identified a group of genes altered in mice that got better on the cells and found that one important change related to a Parkinson's disease related gene, previously not known to be involved in sepsis. Using mice that had this gene knocked out we determined that absence of this DJ-1 gene is associated with protection from sepsis and sepsis-induced heart failure. We also identified regulators of the gene expression linked to survival in septic hearts treated with MSC: the transcription factor Nrf2 and a small interfering RNA molecule called miR-27a-5p - coincidentally these also regulate or are regulated by DJ-1. Our preliminary data suggests that they may protect mice from death and sepsis-induced heart failure. In this grant we will determine the role of these novel molecules in isolated heart and immune cells and transgenic mice lacking the DJ-1 gene. We will also determine if by manipulating the expression of the gene/regulators using viral vectors, cells or cell products we can induce resistance to sepsis. The knowledge we will generate may be used to develop new treatments for this devastating disease.