TAK1 signaling pathways

摘要 先天免疫信号通路被激活，以应对接触微生物，以及 通常通过诱导炎症和宿主细胞死亡来有效地防止病原体的入侵。 然而，它的异常激活被认为与许多炎症性疾病有关。 癌症和神经退化，因为它可能通过炎症和细胞死亡导致组织损伤。这个 先天免疫信号通路是高度复杂的，因为它们是随着进化而进化的 试图逃避宿主免疫的微生物。因此，先天免疫的调节机制 尤其是它们的信令连接/网络还没有完全被理解。了解其中的复杂性 与生俱来的免疫信号网络会影响我们制定对抗策略的能力 用于病原体感染和治疗炎症性疾病。我们一直在研究有丝分裂原激活蛋白 激酶7(MAP3K7)，又称TAK1，自发现以来。最初我们确定了TAK1 通过激活MAPK级联和核因子-κB介导炎症反应的转录激活 小路。最近，通过我们对许多组织特异性Tak1缺陷小鼠的鉴定 我们已经揭示了TAK1也参与了细胞死亡。然而，仍有一些问题没有得到答复 基本问题：为什么以及如何通过TAK1使炎症和细胞死亡途径汇聚？ R35稳定的融资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物调节剂，以及回答 上述核心问题。在接下来的5年里，我们建议确定分子机制如何 炎症和细胞死亡通路在TAK1以及TAK1异常激活如何导致 炎症性疾病。

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.