Ballweg Richard, Schozer Frederick, Elliott Kelsey, Kuhn Alexander, Spotts Logan, Aihara Eitaro, Zhang Tongli
Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
Division of Plastic Surgery, Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
BMC Syst Biol. 2017 Nov 22;11(1):111. doi: 10.1186/s12918-017-0497-y.
Helicobacter Pylori (HP) is the most common risk factor for gastric cancer. Nearly half the world's population is infected with HP, but only a small percentage of those develop significant pathology. The bacteria itself does not directly cause cancer; rather it promotes an environment that is conducive to tumor formation. Upon infection, HP induces transcriptional changes in the host, leading to enhanced proliferation and host immune response. In addition, HP causes direct damage to gastric epithelial cells.
We present a multiscale mechanistic model of HP induced changes. The model includes four modules representing the host transcriptional changes in response to infection, gastric atrophy, the Hedgehog pathway response, and the restriction point that controls cell cycle. This model was able to recapture a number of literature reported observations and was used as an "in silico" representation of the biological system for further analysis. Dynamical analysis of the model revealed that HP might induce the activation of multiple interplayed positive feedbacks, which in turn might result in a "ratchet ladder" system that promotes a unidirectional progression of gastric disease.
The current multiscale model is able to recapitulate the observed experimental features of HP host interactions and provides dynamic insights on the epidemiologically observed heterogeneity in disease progression. This model provides a solid framework that can be further expanded and validated to include additional experimental evidence, to understand the complex multi-pathway interactions characterizing HP infection, and to design novel treatment protocols for HP induced diseases.
幽门螺杆菌（HP）是胃癌最常见的风险因素。世界上近一半的人口感染了HP，但只有一小部分人会发展为严重病变。这种细菌本身不会直接导致癌症；相反，它促进了有利于肿瘤形成的环境。感染后，HP会诱导宿主发生转录变化，导致增殖增强和宿主免疫反应。此外，HP会对胃上皮细胞造成直接损伤。
我们提出了一个HP诱导变化的多尺度机制模型。该模型包括四个模块，分别代表宿主对感染的转录变化、胃萎缩、刺猬信号通路反应以及控制细胞周期的限制点。这个模型能够重现许多文献报道的观察结果，并被用作生物系统的“计算机模拟”表示，以进行进一步分析。对该模型的动力学分析表明，HP可能会诱导多个相互作用的正反馈激活，进而可能导致一个“棘轮阶梯”系统，促进胃部疾病的单向进展。
当前的多尺度模型能够概括HP与宿主相互作用中观察到的实验特征，并为疾病进展中流行病学观察到的异质性提供动态见解。该模型提供了一个坚实的框架，可以进一步扩展和验证，以纳入更多实验证据，理解HP感染所特有的复杂多途径相互作用，并设计针对HP诱导疾病的新型治疗方案。
