Inappropriate and chronic inflammatory responses underly the development of Inflammatory Bowel Diseases (IBD), including both ulcerative colitis and Crohn’s disease. This process is an intertwined, inter-cellular cascade among diverse immune cells and tissue stroma. The interactions between immune and stromal cells not only propagate inflammatory responses but also regulate resolution of inflammation. Yet, we do not understand how immune cells interact with tissue stroma when intestinal inflammation occurs and resolve. We propose to first develop cutting-edge technologies that discover interacting partners of immune cells in vivo in a high-throughput and unbiased manner. We will then apply these new tools to identify the interactomes of immune cells over the course of intestinal inflammation. Funding from the Kenneth Rainin Foundation will support our program to map out the path of immune-stromal interactions from a healthy intestine to an inflamed tissue to recovery and repair. Targeting immune-stromal interactions that cause inflammatory propagation as well as the resolution will establish a new strategy to alleviate inflammation. Our long-term goal is to leverage this knowledge to switch “inflammatory interactions” to “resolving interactions” in order to restore intestinal homeostasis, which will ultimately curtail IBD and its devastating health implications.