Novel regulators of NLRP1 inflammasome

NLRP1 is an immune sensor that initiates the assembly of multi-protein complexes called inflammasomes in response to pathogens and danger signals. While highly potent in inducing immune responses to resolve these dangers, NLRP1 causes a myriad of genetic auto-inflammatory diseases and cancers when dysregulated, and has been associated with common skin diseases such as atopic dermatitis and psoriasis. However, regulatory pathways that keep its activity in check remain poorly understood. To unearth these regulations and develop NLRP1 as a novel therapeutic target, we had performed a genome-wide loss-of-function screen to identify inhibitors and activators of NLRP1. Using biochemical, cell and molecular biology approaches, we will validate candidate genes and elucidate their mechanisms of action. We will study how these genes interplay to impact NLRP1, and whether they play similar or distinct roles across various dangers that NLRP1 responds to. Finally, we will relate these findings to skin physiology by studying how skin stem cells and their differentiated progeny coordinate their activity through proper NLRP1 regulation to maintain a healthy epithelial-immune cell crosstalk and skin barrier function.