We investigate the biology of Crohn’s disease and ulcerative colitis. These are two inflammatory bowel diseases that can affect individuals at any age, most often in early adulthood. They emerge from a complex gene – environment interaction. The actual triggers remain still unknown.
Employing and developing a wide range of technologies, from complex genetic models to sophisticated liquid chromatography mass spectrometry, we explore the major biological mechanisms that are affected by risk genes of inflammatory bowel disease. This has generated important insights into how autophagy and endoplasmic reticulum stress collude to drive a pathological unfolded protein response. And most recently led to the discovery of a very fundamental purine enzyme that enables a metabolic cycle balancing electron transfer into mitochondria and controlling immunometabolism of macrophages.
We also run a clinical trials unit, based at Addenbrooke’s Hospital and the Clinical Research Facility, which translates novel insights into therapeutic opportunities for our patients with inflammatory bowel disease. This ranges from proof-of-concept studies and early phase clinical development programmes of novel mechanisms of action up to late phase pivotal registration trials.
Cader MZ†, Rodrigues RPDA†, West JA†, Sewell GW, Md-Ibrahim MN, Reikine S, Sirago G, Unger LW, Iglesias Romero AB, Ramshorn K, Haag LM, Saveljeva S, Ebel JF, Rosenstiel P, Kaneider NC, Lee JC, Lawley TD, Bradley A, Dougan G, Modis Y, Griffin JL, Kaser A. FAMIN is a multifunctional purine enzyme enabling the purine nucleotide cycle. Cell 2020 Jan 23; 180:278-295 doi:10.1016/j.cell.2019.12.017 † shared first authors
Tschurtschenthaler M, Adolph TE, Ashcroft JW, Niederreiter L, Bharti R, Saveljeva S, Bhattacharyya J, Flak MB, Shih DQ, Fuhler GM, Parkes M, Kohno K, Iwawaki T, van der Woude CJ, Harding HP, Smith AM, Peppelenbosch MP, Targan SR, Ron D, Rosenstiel P, Blumberg RS, Kaser A. Defective ATG16L1-mediated removal of IRE1α drives Crohn’s disease-like ileitis. J Exp Med 2017 Feb;214(2):401-422. doi: 10.1084/jem.20160791.
Cader MZ, Boroviak K, Zhang Q, Assadi G, Kempster SL, Sewell GW, Saveljeva S, Ashcroft JW, Clare S, Mukhopadhyay S, Brown KP, Tschurtschenthaler M, Raine T, Doe B, Chilvers ER, Griffin JL, Kaneider NC, Floto RA, D’Amato M, Bradley A, Wakelam MJO, Dougan G, Kaser A. C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nat Immunol 2016 Sep;17(9):1046-56. doi: 10.1038/ni.3532. Epub 2016 Aug 1.
Niederreiter L, Fritz TMJ, Adolph TE, Krismer A-M, Offner FA, Tschurtschenthaler M, Flak MB, Hosomi S, Tomczak MF, Kaneider NC, Sarcevic E, Kempster SL, Raine T, Rosenstiel P, Kohno K, Iwawaki T, Tilg H, Blumberg RS, Kaser A. ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells. J Exp Med. 2013;210:2041-56.
Adolph TE†, Tomczak MF†, Niederreiter L†, Ko HJ†, Böck J, Martinez-Naves E, Glickman JN, Tschurtschenthaler M, Hartwig J, Hosomi S, Flak MB, Cusick JL, Kohno K, Iwawaki T, Billmann-Born S, Raine T, Bharti R, Lucius R, Kweon MN, Marciniak SJ, Choi A, Hagen SJ, Schreiber S, Rosenstiel P, Kaser A*, Blumberg RS*. Paneth cells as a site of origin for intestinal inflammation. Nature 2013;503:272-6. * shared senior and corresponding authors; † shared first authors
Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 2008;134:743-56.