A novel mouse model to monitor inflammasome activation in vivo

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 DESCRIPTION (provided by applicant): Inflammasome activity is essential for homeostasis, but impaired and excessive activity causes a wide spectrum of human inflammatory disease, and therefore determining inflammasome activity during disease progression in vivo is important to advance our knowledge on the underlying disease pathologies and to develop novel therapies. Currently, however, no approaches exist to monitor and quantify inflammasome activity in vivo, and even ex vivo and in vitro measurements require prolonged manipulation of cells adverse affecting kinetic studies and further, require expensive substrates. We developed a novel dual reporter mouse model allowing luminescent and fluorescent-based in vivo and ex vivo detection and quantification of inflammasome activity without any manipulation. In aim 1 we propose to characterize this novel model in vitro and in vivo, determine its specificity and contrast it with currently state of the art methods. In aim 2 we propose to provide proof-of-principle for this novel model using two complex inflammasome-dependent diseases, namely Cryopyrinopathies (CAPS) and colitis. We expect these studies will ultimately positively affect human health by enabling novel, more relevant studies of inflammasome activity during physiology and pathology and further will be a very useful model for pre-clinical studies investigating inflammasome-targeted therapies.