Grant: Discovery Grants Program - Individual

The process of gene expression is tightly regulated at various levels including transcriptional, translational and post-translational steps. The regulation of gene expression at the translational level allows cells to rapidly reprogram protein output in response to stress stimuli. During stress conditions, canonical mRNA translation is reduced due to modification of key eukaryotic translation initiation factors (eIFs). However, the non-canonical translation allows synthesis of proteins that are required to manage stress conditions. For example, the production of both pro-apoptotic and anti-apoptotic proteins is regulated via non-canonical translation mechanisms under stress conditions. Thus, the non-canonical translation is considered to play a central role during cellular stress response. Accordingly, my ongoing research program is focused on studying the mechanisms of non-canonical translation initiation during cellular stress and apoptosis. Internal ribosome entry site (IRES)-mediated translation is one of the validated non-canonical translation initiation mechanisms that operates under stress conditions. The production of many proteins that affect cell death is regulated by an IRES-dependent mechanism. However, there is a clear gap in the knowledge as to how mRNA translation of these proteins switches from the canonical to IRES-dependent mode. We have identified, eukaryotic initiation factor 5B (eIF5B), as a key driver of IRES-mediated translation initiation. The molecular mechanism of eIF5B's role in IRES-mediated translation initiation is not delineated. In Aim 1 of this proposal, we will elucidate the mechanistic role of eIF5B in IRES-mediated translation initiation under stress conditions. We and others have shown that eIF5B protein levels increase under stress condition. However, it not known how eIF5B protein levels and its activity are regulated in stress condition. In Aim 2 of this proposal, we will perform proteomics analysis of eIF5B interacting partners to identify potential regulators of eIF5B. Moreover, in order to understand the role of eIF5B in cellular stress response, in Aim 3 of this proposal, we will define the eIF5B-regulated transcriptome-wide changes in mRNA translation (translatome) under normal and stress conditions. My research program will provide significant insight into the process of mRNA translation. The knowledge generated will be applicable to the molecular biology research areas of development, and differentiation. Moreover, this proposed study will provide clues toward understanding the relevance of dysregulated mRNA translation in various physiological disorders such as cancer, and Alzheimer's disease. My research program will provide state-of-the-art skills to my trainees in cellular and molecular biology as well as biochemistry research areas using pan-omics technology and prepare them for employment in academia, public sector, and the growing RNA-based industry.