The Role of DHCR7 in Endotoxemia

PROJECT SUMMARY/ABSTRACT Sepsis is a common and deadly disease and treatment options are limited to antibiotics and supportive care. Endotoxemia is a key feature of sepsis pathogenesis and can also contribute to numerous other inflammatory disorders. Growing antibiotic resistance and an aging population have contributed to an urgent unmet need for new therapeutics for these conditions. In Dr. Jacob’s published work, she used the endotoxin lipopolysaccharide (LPS) to recapitulate key features of sepsis pathogenesis. RNA sequencing (RNA-seq) identified cholesterol metabolism as one of the most significantly altered pathways in LPS treated zebrafish and in sepsis patients with poor outcomes. Specifically, the mRNA for 7-dehydrocholesterol reductase (DHCR7), which catalyzes the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol, was significantly upregulated in LPS treated zebrafish and was one of only two lipid- related gene associated with mortality in sepsis patients. Dr. Jacob made the novel finding that fish treated with a DHCR7-specific inhibitor were completely protected from endotoxemic death. Dr. Jacob’s K08 proposal aimed to elucidate the role of DHCR7 in endotoxemia in both zebrafish and mammalian systems and identify clinically utilized DHCR7 inhibitors that mediate LPS toxicity, with implications for the development of sepsis therapeutics. Prior to her leave, Dr. Jacob had generated a stable zebrafish DHCR7 mutant line and had completed proposed experiments in a murine model. This supplement will allow Dr. Jacob to hire additional personnel to complete the remainder of her mechanistic studies on DHCR7 both in vitro and in vivo and make up for time away from the laboratory. Thus, Dr. Jacob will emerge from this supplement period with the ability to expand the translational reach of her findings and successfully compete for independent funding.