Saturday, December 21, 2024
12/21/2024
PROJECT SUMMARY This proposal outlines a training program for independent scientist with a focus on mRNA localization using genetics and molecular biology. The research outlined in this proposal will develop a platform to evaluate local translation, a process of whose disruption results in many neurological diseases and cancer. The phenomena directing local translation to axon termini and the Endoplasmic Reticulum (ER) have been described. Scientists have recently made the novel discovery that local translation also occurs at plasma membranes. For example, in Caenorhabditis elegans, ezrin/radixin/moesin (erm-1) mRNA localizes to plasma membranes with its encoded protein, a plasma membrane-actin cytoskeleton linker that will coordinate cell shape changes. erm- 1/ERM-1 undergoes translation-dependent localization and local translation directed by its N-terminal encoded FERM domain. However, neither the mechanisms directing their localization nor the reasons for their local translation are understood. The proposed research aims to use erm-1 as a model to understand how mRNA localization to the plasma membrane arises mechanistically, functionally links to protein production, and impacts gene expression. Based on preliminary evidence, the hypothesis is that cytoskeletal components interact with the translating complex to direct it to the plasma membrane, similar to co-translational transport of secretory proteins to the ER. This model will be explored from a genetics and molecular biology perspective with 3 specific aims. The first aim will test whether erm-1/ERM-1 localization occurs through diffusion or directed transport mechanisms and explore which cytoskeletal components are required. The second aim will develop a live imaging tool to better resolve the kinetics of erm-1 translation. The third aim will identify the effector proteins involved in this process. Since impaired mRNA localization in neurons and other cell types causes disease but studying mRNA localization in disease-specific models is challenging, this project will achieve our long-term goal of characterizing novel mRNA transport pathways that have the potential to be generalizable in human health.
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