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 Our unpublished results demonstrated that TNFα cytotoxicity in severe sepsis is mediated by massive BAD release from cytoskeleton despite concurrent activation of IKK and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 Our unpublished results demonstrated that IKK signaling network suppresses TNFα-induced apoptosis through coherent feedforward regulation.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

项目摘要/摘要 我们实验室的研究中心了解细胞死亡中的信号传导机制 以及使用IκB激酶（IKK）生存，感染，免疫调查和病原体感染 信号网络是一种分子探针，以探索信号的潜在干预措施 预防和治疗炎症和传染病的机制。 我们接下来五年的目标是：1）了解分子机制 控制炎症和传染病中的TNFα细胞毒性。以前，我们 据报道，TNFα诱导的凋亡受到IKK介导的促进的抑制作用抑制了 凋亡Bcl-2家族成员仅BH3蛋白质不良，除了激活NF-κB之下 生理或发育条件。我们未发表的结果表明TNFα 严重败血症中的细胞毒性是通过细胞骨架目的地的大量不良释放介导的 IKK和NF-κB的同时激活。我们计划确定基本机制和 它在其他TNFα中的其他炎症和传染病中的潜在应用 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 细胞毒性。我们未发表的结果表明IKK信号网络抑制 TNFα通过相干的进发调节诱导的凋亡。我们计划使用 探索基本数学和物理科学的计算建模 概念已被应用于系统的IKK信号网络调节TNFα细胞毒性 级别，从而提出了超出经验数据的新假设以进行进一步测试； 3）非典型IKK-NF-κB网络的新型调节机制。我们未发表的 结果表明，转录因子MIZ1是激活非典型的必需的 淋巴毒素（LT）和其他刺激的NF-κB独立于其转录活性和 缺乏MIZ1的小鼠显示出柠檬酸啮齿动物感染的清除率受损。我们计划 研究潜在机制及其在针对细菌的粘膜免疫反应中的作用 感染。 我们实验室研究计划的总体愿景是提供新颖的策略和 确定预防和治疗炎症和感染性人的分子靶标 疾病。