PROJECT SUMMARY/ABSTRACT Understanding the mechanisms that underlie the function and regulation of immune cells in health and disease is critical to developing therapies aimed at modulating their function. Innate immune cells such as macrophages represent a critical arm of the immune system. These cells not only represent the front line of defense against microbes, but also mediate critical effector functions at the direction of the adaptive immune system. Dysregulation of such effector functions can lead to pathogenic inflammation and tissue damage, as seen in septic shock, an acute condition that results in the death in one out of three affected patients. Thus, understanding the functional regulation of these cells can help to develop therapeutic interventions for such diseases. Classical protein coding genes represent the minority of genetic elements in the eukaryotic genome, and yet these genes have been the focus of the vast majority of functional studies to date, including those investigating innate immune cell function. Surprisingly, the number of such genes does not increase with organismal complexity, while the number of so-called non-coding genes does. This suggests that the latter genes execute complex cell type-specific regulator functions. A class of such genes, called long non-coding RNAs (lncRNAs) have recently emerged as critical regulators of immune cell function. We have identified such a lncRNA, called U90926, as almost exclusively expressed in activated myeloid cells. The function of this gene is unknown. We have generated mice deficient in this gene, and we propose an experimental plan to functionally dissect the role of this gene in myeloid cell effector function, both in vitro and in vivo, in clinically relevant models of human inflammatory disease.