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-?B 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.
Inflammation is an important biological response that protects us from pathogen invasion; however, its aberrant activation causes and promotes a number of age-related diseases. This project seeks to define how aberrant inflammation occurs and causes diseases at a molecular level by investigating one of the central molecules of inflammatory pathways, a protein kinase TAK1. Outcomes could lead to new approaches for inflammatory diseases.