Defining the mechanism of CNS inflammation induced by colitis

About This Grant

Inflammatory Bowel Diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are life-long diseases characterized by cycles of active flares and remission. Disease flares result in significant inflammation in the colon, as well as pathology in other organ systems, including the brain. Central nervous system (CNS) dysfunction is a well-established comorbidity in patients with IBD. We have recently demonstrated CNS inflammation, and specifically inflammasome activation, is induced in the CNS of mice in an acute colitis model using a novel mouse model in which inflammasome activation induces tissue bioluminescence. In this grant, we seek to understand the mechanisms by which CNS inflammation is induced in this and similar models. We seek to extend exciting preliminary data which reveal that colitis results in the presence of a factor or factors in serum that drive CNS inflammation to identify this factor and the mechanism by which is induces inflammasome activation in the CNS. We also propose to use a newer version of our mouse model, in which expression of our luciferase based caspase-1 biosensor is restricted to specific cell lineages in the CNS, allowing us to understand the impact of colitis and CNS inflammation on specific cell populations.