Background: The NAIP/NLRC4 inflammasomes are defenders against cytosolic infections by bacteria such as Salmonella and Pseudomonas through recruitment and activation of pro-caspase-1, lead to the production of interleukin-1β (pro-IL-1β) and IL-18, and induces pyroptotic cell death. The NAIP/NLRC4 inflammasomes are comprised with three components, the bacterial ligands such as flagellin, the NAIPs, and the NLRC4 protein. NAIPs recognize different bacterial ligands and determine the specificity of NAIP/NLRC4 inflammasomes. Abnormal inhibition and activation of these complexes cause human inflammatory diseases, NLRC4 mutation also related with the colitis-associated colorectal cancer (CAC). This project on structural and biochemical studies of the NAIP/NLRC4 inflammasomes will provide important insights into cytosolic bacteria sensing mechanisms and lead to new strategies on disease treatment and drug development. Research/Career Goals: My short-term goal is to understand the structural basis of how NAIP/NLRC4 inflammasome are activated by bacterial ligand, and the long-term goal is to understand the complicated immune responses upon pathogen infection. The specific aims of this project are to elucidate the mechanism of ligand recognition by NAIP and NLRC4, the autoinhibited conformation of NAIP, and to identify small molecule inhibitors of CARD-CARD interactions in inflammasomes. Research/Career Development Plan and Environment: I will take cryo-EM workshops at Harvard Medical School (HMS) and Center for Nanoscale Systems (CNS), learn cell biology and small molecule screening techniques from the mentor's lab, and complete the proposed study. I will attend a series of international conferences to expand my knowledge in immunology. Under the mentorships of Drs. Hao Wu (BCH), Maofu Liao (HMS) and Timothy J. Mitchison (HMS), I will follow the traditional training program to maximize my professional abilities for transition into independence. Program in Cellular and Molecular Medicine (PCMM) at BCH and HMS will provide me with the great environment for scientific achievement and career development to become an independent structural immunologist during this award.