Pyroptosis is a Trial-by-Fire Program

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TITLE Pyroptosis is a Programmed Trial-by-Fire. PROJECT ABSTRACT The inflammatory cell death program pyroptosis occurs in a wide range of cell types and plays important roles in development, tissue injury, and tumor growth. Curiously, unlike other cell death mechanisms, cells frequently survive pyroptosis activation. The persistence of a family of “inefficient” cell death genes is puzzling and suggests they may have other roles. Intuitively, cells that survive the inflammatory insult will dictate both the short-term adaptation and long-term repair and regeneration afterwards. Therefore, a flawed death program may actually be a “trial”. However, the details of cell survival after pyroptosis and the biochemical circuitry beyond its activation are under-studied, hindering our basic understanding. In this Program, we hypothesize that cell death is a side- effect of pyroptosis, which in fact aims to reprogram cell functions. To explore the new concept that “trial-by-fire” provides strong evolutionary advantages, we will investigate 1) whether it is possible to stop/resume pyroptosis and the basic mechanisms used to exert such control; 2) the capacity and limits of pyroptosis signaling; and 3) the single cell phenotypic effects of weathering pyroptosis. In pursuing this central hypothesis, we will discover new cell signaling circuits and simultaneously enhance the field’s ability to detect novel pathways by developing new genetically encoded tools, imaging algorithms, and bioinformatics methods. The Program aims to construct a new perspective that the salient function of pyroptosis is to prime and educate through a near-death experience. The proposed administrative supplement combines sound platforms like Fluorescence Assisted Cell Sorting with new technical developments in protein engineering to boost the scale and speed at which accurate data on pyroptosis signaling can be generated.