IKK signaling network: TNF cytotoxicity, computational modeling and regulation

项目摘要/摘要 我们实验室的研究集中在了解细胞死亡的信号机制上。 和生存，炎症，免疫反应和病原体感染，使用IκB激酶(IKK) 以信号网络为分子探针探索信号转导的潜在干预 预防和治疗炎症和传染病的机制。 我们未来五年的目标是：1)了解 控制炎症性和感染性疾病中的肿瘤坏死因子α细胞毒性。此前，我们 有报道称，肿瘤坏死因子α诱导的细胞凋亡是通过IKK介导的抑制细胞周期蛋白原途径而被抑制的。 凋亡的bcl2家族成员BH3-Only蛋白BAD与核因子-κB的激活 生理或发育状况。我们未发表的结果表明，肿瘤坏死因子α 严重脓毒症的细胞毒性是由细胞骨架的大量不良释放介导的，尽管 IKK和NF-κB的同时激活。我们计划确定其潜在的机制和 肿瘤坏死因子α在其他炎症性和感染性疾病中的潜在应用 细胞毒性在疾病病理中起着至关重要的作用；2)计算模拟肿瘤坏死因子α 细胞毒性。我们未发表的结果表明，ikk信令网络抑制了 肿瘤坏死因子α通过一致性前馈调控诱导细胞凋亡。我们计划使用 探索基础数学和物理科学的计算建模 一些概念已被应用于通过ikk信号网络在系统中调节肿瘤坏死因子α的细胞毒性。 水平，从而在经验数据之外提出新的假设以供进一步检验； (3)新的非规范IKK-NF-κB网络的调控机制。我们未出版的 结果表明，转录因子Miz1是激活非正则基因所必需的 淋巴毒素(LT)和其他不依赖于其转录活性的刺激而产生的核因子-κB Miz1基因缺陷的小鼠表现出对轮状柠檬酸杆菌感染的清除障碍。我们计划 细菌黏膜免疫应答机制及其作用机制的研究 感染。 我们实验室研究计划的总体愿景是提供新的策略和 确定防治人类炎症性和传染性疾病的分子靶点 疾病。

Project Summary/Abstract The research in our laboratory centers on understanding signaling mechanisms in cell death and survival, inflammation, immune responses and pathogen infection, using IκB kinase (IKK) signaling network as a molecular probe to explore potential intervention of the signaling mechanisms for prevention and treatment of inflammatory and infectious diseases. Our goals for the next five years are: 1) understanding the molecular mechanism that controls TNFα cytotoxicity in inflammatory and infectious diseases. Previously, we reported that TNFα-induced apoptosis is suppressed by IKK-mediated inhibition of the pro- apoptotic BCL-2 family member BH3-only protein BAD in addition to activation of NF-κB under physiological or developmental conditions. Our unpublished results demonstrated that TNFα cytotoxicity in severe sepsis is mediated by massive BAD release from cytoskeleton despite concurrent activation of IKK and NF-κB. We plan to determine the underlying mechanism and its potential applications in other inflammatory and infectious diseases in which TNFα cytotoxicity plays a crucial role in disease pathologies; 2) computational modeling TNFα cytotoxicity. Our unpublished results demonstrated that IKK signaling network suppresses TNFα-induced apoptosis through coherent feedforward regulation. We plan to use computational modeling to explore how fundamental mathematics and physical sciences concepts have been applied to regulate TNFα cytotoxicity by IKK signaling network at systems level, thereby putting forward novel hypotheses beyond the empirical data for further testing; and 3) novel regulatory mechanism of non-canonical IKK-NF-κB network. Our unpublished results demonstrated that the transcription factor Miz1 is required for activation of non-canonical NF-κB by lymphotoxin (LT) and other stimuli independently of its transcriptional activity and Miz1-deficient mice display impaired clearance of Citrobactor rodentium infections. We plan to study the underlying mechanism and its role in mucosal immune responses against bacterial infection. The overall vision of the research program in our laboratory is to provide novel strategies and identify molecular targets for prevention and treatment of inflammatory and infectious human diseases.