Previous title:Genetic basis of autoimmune pancreatitis Refined title:Experimental studies on Map3k7 and Bach2 as risk genes of autoimmune pancreatitis

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The project focuses on the genetic basis of autoimmune pancreatitis (AIP), a rare but clinically important variant of chronic pancreatitis. Employing both a mouse model of AIP and human samples, the applicants succeeded in the first funding period (until 2018) in the identification of potential risk genes of AIP. Although these results were acknowledged by the reviewers of the grant renewal application, the proposal itself was not ranked high enough for further funding. In the meantime, we have made significant progress by mapping two previously unknown risk genes of experimental AIP, as also documented by additional publications. The two genes, Bach2 (BTB domain and CNC homolog 2) and Map3k7 (Mitogen-activated protein kinase kinase kinase 7), encode for a transcriptional repressor and an intracellular protein kinase, respectively, that play central roles in immune homeostasis and have previously been linked to autoimmune processes. It is assumed that both genes, independent from each other, may contribute to the genetic risk of AIP. We are now planning to functionally characterize Bach2 and Map3k7 in the context of AIP. Therefore, we will take advantage of Bach2-deficient mice with an AIP-susceptible C57BL/6background to challenge the hypothesis that lack of Bach2 aggravates murine AIP by enhancing infiltration of pancreatic tissue with autoreactive T-cells and stimulating production of autoantibodies by activated B-cells. Previous studies have shown that important target genes of Bach2 can be inhibited by the Janus kinase inhibitor tofacitinib. Therefore, we will also investigate therapeutic efficiency of this drug in the context of experimental AIP by employing MRL/MpJ mice, which spontaneously develop AIP early in lifetime. Furthermore, immune cells of diseased mice and control animals will be subjected to in-depth studies. In case of Map3k7, we postulate a positive correlation between expression/activity and exhibition of AIP. Again, the hypothesis will be challenged by combining studies at the molecular and cellular level with mouse experiments, which will also address therapeutic efficiency of the specific inhibitor takinib. After the second period of funding, the entire project shall be completed successfully. In addition to pathomechanistic understanding, we expect from our studies also the identification of novel targets for diagnostics and therapy of the disease.