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 Our unpublished results demonstrated that TNFα cytotoxicity in severe sepsis is mediated by massive BAD release from cytoskeleton despite concurrent activation of IKK and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 Our unpublished results demonstrated that IKK signaling network suppresses TNFα-induced apoptosis through coherent feedforward regulation.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

项目概要/摘要 我们实验室的研究重点是了解细胞死亡的信号机制 使用 IκB 激酶 (IKK) 和生存、炎症、免疫反应和病原体感染 信号网络作为分子探针探索信号传导的潜在干预 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）了解分子机制 控制炎症和传染病中的 TNFα 细胞毒性。 报道称，IKK 介导的前体抑制作用可抑制 TNFα 诱导的细胞凋亡。 凋亡 BCL-2 家族成员 BH3-only 蛋白 BAD 以及 NF-κB 的激活 我们未发表的结果表明 TNFα。 严重脓毒症的细胞毒性是由细胞骨架中大量 BAD 释放介导的，尽管 我们计划确定 IKK 和 NF-κB 的同时激活的潜在机制和 其在其他炎症和感染性疾病中的潜在应用，其中 TNFα 细胞毒性在疾病病理学中起着至关重要的作用；2) TNFα 计算模型 我们未发表的结果表明 IKK 信号网络会抑制细胞毒性。 我们计划使用连贯的前馈调节来诱导细胞凋亡。 计算建模探索基础数学和物理科学如何 概念已应用于通过 IKK 信号网络在系统中调节 TNFα 细胞毒性 水平，从而提出超越经验数据的新假设以供进一步检验； 3）非经典IKK-NF-κB网络的新调控机制。 结果表明，转录因子 Miz1 是非规范激活所必需的。 NF-κB 受淋巴毒素 (LT) 和其他刺激影响，与其转录活性无关 Miz1 缺陷小鼠对柠檬酸杆菌感染的清除能力受损。 研究其在针对细菌的粘膜免疫反应中的潜在机制及其作用 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 确定预防和治疗人类炎症和传染性疾病的分子靶点 疾病。