IKK signaling network: TNF cytotoxicity, computational modeling and regulation

IKK 信号网络：TNF 细胞毒性、计算模型和调控

• 批准号: 9532911
• 负责人: ANNING LIN
• 金额: $ 44.62万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-21 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9532911
• 关键词: Apoptosis; Apoptotic; BCL2 gene; Bacterial Infections; Bad protein; Cell Death; Cell Survival; Communicable Diseases; Computer Simulation; Cytoskeleton; Data; Development; Disease; Family member; Genetic Transcription; Goals; Immune response; Impairment; Infection; Inflammation; Inflammatory; Intervention; Laboratories; Light; Mediating; Molecular; Molecular Probes; Molecular Target; Mucosal Immune Responses; Mus; Pathology; Phosphotransferases; Physiological; Play; Prevention; Protein Family; Regulation; Reporting; Research; Role; Sepsis; Signal Transduction; Stimulus; System; TNF gene; Testing; Tumor Necrosis Factor-Beta; Virus Diseases; Vision; cytotoxicity; data modeling; human disease; mathematical sciences; novel; novel strategies; pathogen; physical science; programs; transcription factor; tumorigenesis

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 Our unpublished results demonstrated that TNFα cytotoxicity in severe sepsis is mediated by massive BAD release from cytoskeleton despite concurrent activation of IKK and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 Our unpublished results demonstrated that IKK signaling network suppresses TNFα-induced apoptosis through coherent feedforward regulation.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.

项目总结/摘要 我们实验室的研究集中在了解细胞死亡的信号机制 以及存活、炎症、免疫应答和病原体感染，使用IκB激酶（IKK） 信号网络作为分子探针，以探索信号转导的潜在干预 预防和治疗炎性和传染性疾病的机制。 我们未来五年的目标是：1）了解 控制炎症和感染性疾病中的TNFα细胞毒性。此前我们 报道，TNFα诱导的细胞凋亡被IKK介导的对前凋亡的抑制所抑制。 凋亡BCL-2家族成员BH 3-only蛋白BAD除了在凋亡诱导下激活NF-κB外， 生理或发育条件。我们未发表的结果表明，TNFα 严重脓毒症中的细胞毒性是由细胞骨架大量释放BAD介导的， IKK和NF-κB的同时激活。我们计划确定潜在的机制， 它在其他炎症和感染性疾病中的潜在应用， 细胞毒性在疾病病理学中起着至关重要的作用; 2）计算建模TNFα 细胞毒我们未发表的结果表明IKK信号网络抑制了 TNFα通过相干前馈调节诱导细胞凋亡。我们计划使用 计算建模来探索基础数学和物理科学 概念已被应用于通过IKK信号网络调节TNFα细胞毒性， 水平，从而提出新的假设以外的经验数据，以进一步检验; 3）非经典IKK-NF-κB网络的新调控机制。我们未发表 结果表明，转录因子Miz 1是激活非典型细胞所必需的。 NF-κB通过光敏素（LT）和其他刺激独立于其转录活性， Miz 1缺陷型小鼠显示出对啮齿类柠檬酸杆菌感染的清除受损。我们计划 研究其在粘膜免疫应答中的作用及其机制 感染 我们实验室研究计划的总体愿景是提供新的策略， 鉴定用于预防和治疗炎症性和感染性人类分子靶标 疾病