Grant: Operating Grant

Inflammation is a general host response to pathogens and tissue injury. The process is initiated by cells already present in the damaged tissue, which get activated and release inflammatory mediators. These, in turn, signal the recruitment of leukocytes to the site of injury. Inflammatory activation is crucial for the proper control of infection and for efficient wound healing. However, an enormous proportion of the global burden of disease involves chronically sustained inflammation as in multiple sclerosis (MS) and inflammatory bowel disease (IBD) among others. Thus, a major challenge to public healthcare is the development of targeted therapeutics that can regulate inflammation and thereby improve disease severity and patient outcome. We have created several animal models of susceptibility or resistance to Plasmodium berghei-induced cerebral malaria and Herpes Simplex Virus-induced encephalitis, which mimic extreme pathophysiological steps of neuroinflammation. Research described here will use these models to elucidate key cellular and biochemical pathways at play in common inflammatory diseases. In particular, we will characterize the role of these genes in infection-induced inflammation and further explore their role in mouse models of CNS inflammation and colitis. To validate their role in the human population, we will investigate their expression in human cells from normal and MS or IBD patients. Finally, we will examine possible associations between these genes and the genes that they regulate with IBD and MS. Ultimately, we expect this study to highlight cellular pathways that regulate pathologic inflammation and that might be manipulated pharmacologically to improve patient outcome.