ABSTRACT
Mechanisms driving inflammation, and the possibilities for therapeutic intervention, have expanded dramatically
since the discovery that the intestine is linked to inflammatory diseases involving non-intestinal organs. The
processes and cell types underpinning this inter-organ link are poorly understood, even for diseases which are
coincident with intestinal inflammation. One prominent disease with clear links to intestinal inflammation is
primary sclerosing cholangitis (PSC), an immune-mediated disease hallmarked by liver fibrosis. There is no
therapy that prevents PSC from getting worse, and liver transplant is the only cure—although sometimes, PSC
can return even after liver transplant. The driving forces behind PSC-linked liver fibrosis are thought to originate
in the intestine and thus, understanding the inflammatory processes that link intestinal inflammation with liver
fibrosis would be a breakthrough for this disease. Moreover, these fundamental discoveries would shine new
light into processes that link the intestine to inflammation involving non-intestinal organs, an area that holds
potential for transformative therapeutics. This project will unlock some of this potential by dissecting cellular
mechanisms linking intestinal inflammation with liver fibrosis in a novel mouse model where these diseases occur
concomitantly. These studies will offer specific cell types for targeted approaches to treat diseases linked to the
intestine, including PSC-linked liver fibrosis, an unstoppable disease that has no cure.