In vivo functional characterization of a novel protein encoded by a lncRNA - Project Abstract/Summary 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. Classic protein coding genes represent a 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. 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. We found that this lncRNA can also serve as an mRNA, encoding a novel secreted protein. The source, localization, and function of this protein in vivo is unknown, and represent a significant challenge and a key next question. Here we propose to generate novel mouse models to address all three of these questions in vivo, in models of septic shock.
