The role of selenoproteins in oxidative stress-related gastrointestinal diseases

• Applicant: Dr. Bodo Speckmann
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2011 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 194290907

Research to be conducted within the extended funding period aims to finalise and publish the two following sub-projects: 1. Analysis of intestinal expression and functions of selenoprotein S 2. Basolateral secretion of selenoprotein P from the intestinal epithelium. 1. Selenoprotein S (SelS) has been linked to regulation of inflammation as variants of the gene encoding SelS have been associated with plasma levels of major proinflammatory cytokines. Expression of SelS has so far been detected in macrophages, astrocytes and hepatoma cells, in which SelS localizes to the ER membrane. We hypothesize Selenoprotein S (SelS) to be an important regulator of intestinal inflammation and herein aim at establishing its function in intestinal epithelial cells in relation to IBD pathology. Our unpublished data provides first time evidence of SelS expression in the -human and murine- small and large intestine, with paneth cells of the small intestine and macrophages showing highest SelS levels. We found induction of SelS expression in models of experimental colitis, while this seems to be compromised in patients with active Crohns disease. SelS is expressed in secretory colon-derived cell lines, where it responds to selenium supplementation and to endoplasmic reticulum (ER) stress. Our results show that knockdown of SelS disturbs signaling events occuring after induction of ER-stress, and further indicate that SelS modulates the inflammatory response in these cells. We will study which of the three known signaling pathways that mediate the ER stress response are effected by SelS and analyse how SelS impacts the inflammatory response in intestinal epithelial cells. Additionally, we plan to assess intestinal SelS expression in a larger sample cohort of well documented biopsies taken from IBD patients and control samples provided through our collaborators, Prof. McGuckin and Dr. Graham Radford-Smith, to complement data retrieved from mouse IBD models.2. Resorption of ingested selenium takes place mainly in the small intestine, but mediators of enterocytic uptake and release of selenium species remain largely unknown. Selenoprotein P (SeP), the transport protein for selenium in plasma, is secreted mainly by hepatocytes, but its expression has also been detected in extrahepatic tissues. We have found that polarised Caco-2 intestinal epithelial cells secrete SeP from the basolateral membrane, suggesting its involvement in the uptake of dietary selenium from the gut lumen into the circulation. The group of our collaborator Prof. McGuckin has established ex vivo cultivation of human intestinal explants that we will employ to corroborate our findings of polarised SeP secretion from intestinal epithelia. We have further detected diminished ileal SeP expression in patients with Crohns disease, which is a possible cause for reduced plasma selenium levels that had been found in IBD patients.

• DFG Programme: Research Fellowships
• International Connection: Australia
• Host: Professorin Dr. Kum Kum Khanna