Grant: Fellowship: Bisby (Prize)

This project aims to advance our understanding concerning the mechanisms that regulate the cellular display of ligands for the NKG2D receptor. Engagement of the ligands by NKG2D induces NK cell mediated lysis and cytokine release. Studies indicate that this receptor ligand system plays important roles in tumor surveillance as well as pathogen recognition, and when disregulated contributes to autoimmunity and chronic inflammatory diseases. NKG2D ligands are thought to be regulated by stress pathways and other pathways designed to sense evidence of infection or transformation. Much remains to be learned about this process, however, and the available knowledge is still lacking in critical mechanistic detail. My host laboratory uncovered in the past different novel modes of regulation of NKG2D ligands. In the current project, I propose to develop a deeper understanding of how disease associated stress is read out and translated into events that render cells sensitive to elimination by NK cells. This will be accomplished by uncovering the specific molecular pathway that regulates the transcription of the NKG2D ligand, Rae1e in response to proliferative signals. Finally, I will test the hypothesis that multiple disease-associated signals must converge to render cells sensitive to NKG2D-dependent surveillance, including signals associated with proliferation and others associated with tumor suppressor activation and other stress pathways. The hypothesis is that such signals, together, comprise a "cancer-associated pattern" that enables NK cells to attack the cells. New targets for enhancing tumor immunity or repressing chronic inflammatory diseases may be revealed by these studies.