Tec kinase ITK-dependent signaling pathways in the resolution of inflammation in ulcerative colitis

点击翻译按钮获取中文摘要

Our initial studies on Itk and Itk-interacting proteins were obtained in the last funding period of the SFB1181. We found that the Tec kinase ITK regulates T-cell cytokine production in IBD and experimental colitis, thereby maintaining mucosal inflammation and subsequently preventing disease healing. Interestingly, ITK signalling was activated in UC but not CD patients, and prevented T cell apoptosis as, well as inducing T cell specific cytokines. Furthermore, ITK is a target of the immunosuppressive drug CsA, which is used for clinical therapy of UC. The reason for the different activation of the ITK signalling pathway in UC and CD as well as the role of adaptor proteins or signalling molecules in the ITK signalling pathway needs further investigation. In this project, we aim to gain further insights into the regulatory role of the molecules ZAP70, Lck and TIM1/3 in controlling ITK expression and function in mucosal inflammation, as well as in controlling the production of T cell-specific cytokines. In addition, we will investigate the expression of these proteins in large cohorts of UC patients as well as in mouse models of chronic intestinal inflammation. We will use genetically modified mice (complete and T-cell specific deletion) for these proteins to study their functional role in acute and chronic intestinal inflammation in vivo. Moreover, we will modulate the function of ZAP70, Lck and TIM1/3 in experimental colitis using neutralising antibodies, siRNA or TIM3 ligands, such as galectin-9. In translational experiments, we will test the effect of specific inhibitors of ZAP70, ITK, Lck and TIM1/3 on the activation of mucosal T cells derived from UC patients in cell cultures. Finally, we will determine the effects of these inhibitors using T cell/intestinal organoid cultures as well as tissue section cultures to investigate ITK pathway-dependent regulation of cytokine production and barrier function. Taken together, these studies should provide new insights into the functional role of the ITK pathway in controlling the inflammatory response and lead to novel therapeutic approaches for the treatment of ulcerative colitis.