Understanding the biological role of kB-Ras proteins, potential regulators of chronic inflammation

The transcription factor Nuclear Factor-kappa B (NF-kB) plays a pivotal role in the immune system and deregulation of NF-kB signaling has been associated with various diseases, including chronic inflammation, autoimmune diseases and cancer. Deregulated, persistent NF-kB activity and consequent chronic inflammation have been implicated in the development and progression of atherosclerosis. Since atherosclerosis and resulting cardiovascular diseases, such as coronary artery disease, heart failure or stroke, are constantly increasing in the Western World, understanding the molecular mechanisms governing NF-kB activation in these pathological settings is of great interest. Two potential novel regulators of NF-kB signaling, kB-Ras1 and kB-Ras2, have been identified in our laboratory. Biochemical experiments have suggested that the kB-Ras proteins can act as negative regulators of NF-kB activity and might thus be involved in preventing persistent NF-kB activation. However the molecular mechanisms underlying κB-Ras function in NF-kB signaling remain poorly understood and their biological roles are unclear. To further explore these questions, we have generated conventional and conditional κB-Ras knock-out mice. My preliminary experiments using these mice support the previous hypothesis that kB-Ras proteins function in NF-kB signaling, probably through affecting the inhibitory protein IkBb. Furthermore, my studies have revealed a novel connection between kB-Ras proteins and the Ral GTPases. With the experiments proposed in this application I will investigate the function of κB-Ras proteins in the NF-kB and Ral pathways on a mechanistic level, as well as study the role of the kB-Ras proteins in NF-kB signaling in vivo. To elucidate the function of kB-Ras proteins in the regulation of inflammation, I will examine the effect of kB-Ras deficiency on macrophages in the context of initiation and maintenance of an inflammatory response where deregulated NF-kB activity has been demonstrated to be pivotal for the pathology of chronic inflammation. The expected results will advance our understanding of the complex regulation of NF-kB activation in immune cells. By pursuing the strategies outlined in this proposal I aim to establish kB-Ras proteins as crucial regulators of inflammatory responses and thus potential novel therapeutic targets in chronic inflammation. (AHA Program: Postdoctoral Fellowship)