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

该项目专注于自身免疫性胰腺炎(AIP)的遗传基础，AIP是慢性胰腺炎的一种罕见但具有临床重要性的变种。申请者同时使用小鼠模型和人类样本，在第一个资助期(直到2018年)成功地识别了AIP的潜在风险基因。虽然这些结果得到了延长赠款申请的审查员的认可，但该提案本身的排名不够高，不足以提供进一步的资金。与此同时，我们通过定位两个先前未知的实验性AIP的风险基因已经取得了重大进展，其他出版物也记录了这一点。这两个基因，Bach2(BTB结构域和Cn同源物2)和Map3k7(丝裂原激活蛋白激酶7)，分别编码转录抑制因子和细胞内蛋白激酶，在免疫动态平衡中发挥核心作用，以前与自身免疫过程有关。假设这两个基因相互独立，可能与AIP的遗传风险有关。我们现在正计划在AIP的背景下对Bach2和Map3k7进行功能性描述。因此，我们将利用具有AIP易感背景的Bach2缺陷小鼠来挑战这样的假设，即缺乏Bach2通过促进自身反应性T细胞对胰腺组织的渗透和刺激激活的B细胞产生自身抗体来加重小鼠AIP。以前的研究表明，重要的Bach2靶基因可以被Janus激酶抑制剂tofacitinib抑制。因此，我们还将在实验性AIP的背景下，通过使用在生命早期自发发生AIP的MRL/MPJ小鼠来研究该药物的治疗效率。此外，将对患病小鼠和对照动物的免疫细胞进行深入研究。对于Map3k7，我们假设AIP的表达/活性与展示呈正相关。再一次，通过将分子和细胞水平的研究与小鼠实验相结合，这一假说将受到挑战，这也将解决特定抑制剂takinib的治疗效率。在第二期资助后，整个项目将圆满完成。除了病理机制的理解，我们还期望从我们的研究中识别出诊断和治疗该病的新靶点。

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.