Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a significant health problem affecting approximately 1.4 million people in the United States and its incidence continues to rise globally. While the risk factors that predispose individuals to development of IBD are incompletely understood, recent evidence indicates that mutations that perturb cellular responses to stress significantly increase the risk of developing intestinal inflammation. In this proposal, we explore our novel hypothesis that mutations in the ribosomal protein L22 (Rpl22) exacerbate intestinal inflammation. In particular, we propose that Rpl22, an RNA-binding protein, serves to limit inflammation during colitis by controlling the endoplasmic reticulum (ER) stress response, most likely through direct binding to target mRNAs. We have shown that inactivation of either one or two Rpl22 alleles causes enhanced intestinal inflammation in a murine colitis model and alters the ER stress response. These observations provide a firm foundation for our proposal to investigate the mechanistic basis by which Rpl22 regulates inflammation by completing two specific aims. In Aim 1, we will explore the populations of infiltrating immune cells in colitis to determine how these populations are altered by mutation of Rpl22 and then use gain- and loss-of-function analysis to explore their role in colitis. Preliminary data indicate that neutrophil infiltration is enhanced in Rpl22 mutant mice; moreover, these neutrophils exhibited features characteristic of enhanced ER stress. Aim 2 seeks to determine how the signaling pathways controlling ER stress, and their downstream molecular effectors, are perturbed by mono- or bi-allelic inactivation of Rpl22. We will also perform an unbiased analysis of the mRNA targets to which Rpl22 binds by employing RNA-Seq methodology. Through these efforts, we expect to gain substantial insight into how Rpl22 may serve as an integrator that links defects in cellular stress responses to inflammation in the gut. PUBLIC HEALTH RELEVANCE: Those afflicted with IBD experience diminished quality of life and diminished life expectancy, as this disease is associated with significant morbidity and mortality. While treatments have improved in the last two decades, there is no cure. By gaining insight into the stress signaling pathways perturbed by mutations in Rpl22, we may identify novel targets for therapeutic intervention.
NIH ExPorter
NIH ExPorter