Project Summary Approach: We will test how the human transcription factor CREM (cAMP responsive element modulator) protects from colitis due to Entamoeba histolytica and inflammatory bowel disease (IBD). Successful completion of these studies will identify how and where CREM acts to guard against bowel injury. Significance: The importance of this project derives from the contribution of amebiasis to diarrhea in children in the developing world and to the estimated one million Americans who suffer from IBD. Understanding how CREM protects may provide new approaches to the currently inadequate treatments of amebic colitis and IBD. Progress: The past 5 years of support advanced the understanding of amebic colitis and resulted in 26 original research papers, including Nature, Nature Microbiology, Scientific Reports and Cell Reports, and publication of 17 reviews. Innovative aspects of the proposal include that cAMP-regulated gene expression has not previously been considered to contribute to defense of the intestine. The environment for the work is a parasitology lab with ongoing investigation of amebiasis in humans, murine models and at the cellular level, which is led by the Principal Investigator with 3 decades of amebiasis research experience.