The production of proteins is precisely regulated in innate immune responses, such as the inflammatory response, to control infection and limit the detrimental effects of inflammation. Malfunction of this regulation can result in many diseases, such as autoimmune disorders (e.g. rheumatoid arthritis) and inflammatory diseases (e.g. Crohn's diseases and the inflammatory bowel disease). There are several ways to control how many proteins a cell produces. For example, cells might regulate how many messenger RNA molecules (also called mRNAs for short) are produced from a gene, or control how many proteins are translated from those mRNA molecules. Previous studies of how inflammatory responses are regulated have largely focused on how mRNA production is controlled. Much less is known about the role that regulating mRNA translation has on the inflammatory response. Recently, we uncovered widespread regulations of protein synthesis during the macrophage-mediated inflammatory response by parallel RNA and ribosome profiling on LPS-activated bone marrow derived macrophages. Specifically, we identified hundreds of differentially translated mRNAs, including those encoding key inflammatory cytokines, such as TNF, and their 3' untranslated regions have significantly enriched binding motifs of several RNA-binding proteins. In this study, we will mechanistically dissect the mRNA translational regulatory networks mediated by one such RNA-binding protein, Cpeb4, which is associated with human inflammatory bowel disease. Our goals are: a) identify and characterize Cpeb4's target mRNAs in the activated macrophages; b) determine how Cpeb4 regulates mRNA translation in the macrophages at molecular level. The results from this study will not only reveal novel mRNA translational regulatory networks in the macrophage mediated inflammatory response, but also provide molecular mechanistic insights into how Cpeb4 is involved in the pathogenesis of the inflammatory bowel diseases.
This study will determine how protein synthesis is regulated during inflammation. We will focus on one protein, Cpeb4, which is involved in human inflammatory bowel disease, to determine its molecular mechanisms in modulating protein synthesis in the macrophage-mediated inflammatory response.
