Microsimulation of anthracis-immune system interaction

描述(由申请人提供)： 该项目将开发一种逼真的微观模拟炭疽杆菌感染的发病机制以及针对它的免疫反应。这个计算模型旨在补充正在进行的体外和动物研究，并提供一种手段来整合在这些不同的实验中获得的信息。 研究人员将研究免疫系统在应对炭疽杆菌感染时的瞬时功能重组。炭疽致命毒素似乎主要通过裂解信号级联中的蛋白质来发挥作用，该信号级联控制包括肿瘤坏死因子和白介素1[β]在内的促炎细胞因子的合成。这种干扰导致这些细胞因子的过度产生，这些细胞因子是宿主抗菌反应的关键成分，但也介导了休克和细胞毒性。导致炭疽病发病的不只是促炎细胞因子本身的过度产生，而是免疫系统正常的短暂重组的失调，其中肿瘤坏死因子和白介素1[β]是其中的关键部分。 微观模拟将被构建为一个模块化和多尺度的现实计算模型，提供探索这一假说的手段，为其证伪设计设计实验测试，并检查其对新疗法设计的影响。

DESCRIPTION (provided by applicant): This project will develop a realistic microsimulation of the pathogenesis of B. anthracis infection and the immune response mounted against it. This computational model is intended to complement the ongoing in vitro and animal studies and provide a means to integrate the information obtained in these various experiments. The investigators will study the transient functional reorganization of the immune system in response to B. anthracis infection. Anthrax lethal toxin appears to act largely by cleaving proteins in the signaling cascade that controls the synthesis of pro-inflammatory cytokines including TNF and IL-1 [beta]. This interference results in the overproduction of these cytokines, which are a key component of the host antibacterial response, but also mediate shock and cytotoxicity. It is not simply the overproduction of pro-inflammatory cytokines per se that drives the pathogenesis of anthrax, but the dysregulation of the normal transient reorganization of the immune system of which TNF and IL-1[beta] are a key part. The microsimulation will be constructed as a modular and multi-scale realistic computational model providing the means to explore this hypothesis, design experimental tests for its falsification and examine its implications for the design of novel therapies.