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Activation of alternative NF-kB signaling in the stomach: link to H. pylori virulence factors and effect on gastric inflammation and gastric pathogenesis

胃中替代 NF-kB 信号的激活：与幽门螺杆菌毒力因子的联系以及对胃炎症和胃发病机制的影响

基本信息

批准号：
312925791
负责人：
Professor Dr. Markus Gerhard
金额：
--
依托单位：
Institut für Medizinische Mikrobiologie, Immunologie und Hygiene
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/312925791?language=en
关键词：
Activation alternative NF kB signaling

项目摘要

Helicobacter pylori (H. pylori) infection is one of the most prevalent infections worldwide. The chronic gastric inflammation induced by the bacterium might eventually progress to a more severe pathology and finally to gastric cancer. In this process, different host signaling pathways triggered by H. pylori play a decisive role. Of those, the role of canonical NF-kB pathway during H. pylori infection has been extensively studied. Conversely, the involvement of the alternative, so called non-canonical, arm of NF-kB signaling for gastric pathology related to H. pylori remains unclear. We have made preliminary findings indicating involvement of this alternative arm in H. pylori induced inflammatory response. Thus, we propose to perform a comprehensive analysis in vitro as well as in vivo in order to investigate the activation of alternative NF-kB signaling by H. pylori through lymphotoxin b receptor (LTbR) and to elucidate the molecular mechanisms implicated, paying special attention to bacterial virulence factors involved. In addition, by blocking or agonistically activating LTbR in vivo, we aim at deciphering the contribution of alternative NF-kB activation via LTbR-signaling to gastric pathology induced by H. pylori infection. Finally, we plan to specifically express LTs in the stomach to evaluate its involvement in gastric pathogenesis with and without H. pylori infection. Taken together, these experiments will enable us to establish a causal link between LT expression and LTbR-mediated activation of alternative NF-kB to gastric pathogenesis, particularly in the context of H. pylori infection.

幽门螺杆菌（h.p ylori）感染是世界上最普遍的感染之一。由细菌引起的慢性胃炎症可能最终发展为更严重的病理，最终发展为胃癌。在这一过程中，幽门螺杆菌触发的不同宿主信号通路起着决定性的作用。其中，典型NF-kB通路在幽门螺杆菌感染中的作用已被广泛研究。相反，与幽门螺杆菌相关的胃病理中NF-kB信号的另一种，即所谓的非规范臂的参与尚不清楚。我们已经取得了初步的发现，表明在幽门螺杆菌诱导的炎症反应中，这种替代臂的参与。因此，我们建议在体外和体内进行综合分析，以研究幽门螺杆菌通过淋巴毒素b受体（LTbR）激活替代NF-kB信号，并阐明所涉及的分子机制，特别关注所涉及的细菌毒力因素。此外，通过在体内阻断或拮抗激活LTbR，我们旨在破译通过LTbR信号替代NF-kB激活对幽门螺杆菌感染诱导的胃病理的贡献。最后，我们计划在胃中特异性表达LTs，以评估其在有无幽门螺杆菌感染的胃发病机制中的作用。综上所述，这些实验将使我们能够建立LT表达和ltbr介导的替代NF-kB激活与胃发病机制之间的因果关系，特别是在幽门螺杆菌感染的背景下。