TAK1 signaling pathways

TAK1信号通路

• 批准号: 10318180
• 负责人: Jun Ninomiya-Tsuji
• 金额: $ 37.05万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10318180
• 关键词: Biological; Cell Death; Complex; Disease; Exposure to; Funding Mechanisms; Genetically Engineered Mouse; Immune signaling; Immunity; Infection; Inflammation; Inflammatory; Inflammatory Response; Lead; MAP Kinase Gene; MAP3K7 gene; Malignant Neoplasms; Mediating; Molecular; Natural Immunity; Nerve Degeneration; Outcome; Pathway interactions; Pharmacology; Protein Kinase; Signal Pathway; Signal Transduction; Tissues; Transcriptional Activation; age related; experience; fighting; microorganism; mouse model; novel strategies; pathogen; prevent; response

Abstract Innate immune signaling pathways are activated in response to exposure to microorganisms, and generally are effective in preventing pathogen invasion through inducing inflammation and host cell death. However, its aberrant activation is known to be causally associated with many inflammatory diseases e.g. cancers and neurodegeneration, as it could cause tissue damage through inflammation and cell death. The innate immune signaling pathways are highly complex as they have evolved in response to evolving microorganisms trying to evade the host immunity. Thus, the regulatory mechanisms of innate immunity particularly their signaling connections/networks are incompletely understood. Understanding the complexities of the innate immune signaling network is highly anticipated to impact our ability to develop strategies to fight pathogen infection and to treat inflammatory diseases. We have been studying mitogen-activated protein kinase kinase kinase 7 (MAP3K7), known as TAK1, since its discovery. Initially we identified that TAK1 mediates transcriptional activation of inflammatory responses by activating both MAPK cascades and NF-κB pathways. More recently, through our characterization of numerous tissue-specific Tak1-deficient mouse models we have revealed that TAK1 also participates in cell death. However, there remain unanswered fundamental questions; why and how do the inflammatory and cell death pathways converge through TAK1? The R35 stable funding mechanism is highly suitable for this challenging project. We have all the materials, e.g. genetically engineered mouse models and pharmacological modulators, and experience for answering the above central question. For the next 5 years, we propose to determine the molecular mechanisms of how inflammatory and cell death pathways are connected at TAK1 and of how aberrant activation of TAK1 leads to inflammatory diseases.

摘要 天然免疫信号传导途径响应于暴露于微生物而被激活， 通常通过诱导炎症和宿主细胞死亡有效地防止病原体入侵。 然而，已知其异常激活与许多炎性疾病（例如， 癌症和神经变性，因为它可能通过炎症和细胞死亡引起组织损伤。的 先天性免疫信号传导途径是高度复杂的，因为它们是响应于进化的免疫系统而进化的。 试图逃避宿主免疫力的微生物。因此，先天免疫的调节机制 特别是它们的信令连接/网络没有被完全理解。理解复杂性 先天免疫信号网络的研究被高度预期会影响我们制定对抗 病原体感染和治疗炎性疾病。我们一直在研究丝裂原活化蛋白 激酶7（MAP 3 K7），被称为TAK 1，自发现以来。最初我们发现TAK 1 通过激活MAPK级联和NF-κB介导炎症反应的转录激活 路径。最近，通过我们对许多组织特异性Tak 1缺陷小鼠的表征， 我们已经揭示了TAK 1也参与细胞死亡。然而， 基本问题：炎症和细胞死亡途径为何以及如何通过TAK 1汇聚？ R35稳定的资金机制非常适合这个具有挑战性的项目。我们有所有的材料， 例如基因工程小鼠模型和药理学调节剂，以及回答 高于中心问题。在接下来的5年里，我们建议确定如何在分子机制 炎症和细胞死亡途径在TAK 1连接，以及TAK 1的异常激活如何导致 炎症性疾病。