Our long-term research goal is to understand how striated muscle adapts its molecular composition in response to altered physiological demand. This project explores the link between mechanical work, intracellular signals and local control of protein synthesis. The overall hypothesis is that mechanical strain is a primary physiological signal that controls translation and regional protein synthesis.
Specific Aim 1. To show how mechanical load regulates translation by modulation of the interaction between the 3'UTR of alpha-MyHC mRNA and mRNA binding proteins. We expect to find that mechanical activity triggers a specific intracellular signaling pathway. We propose that phosphorylation of specific mRBFs modulates their binding to a specific cis-sequence on the alpha-MyHC 3'UTR, thus controlling translation.
Specific Aim 2. To show that mechanical load regulates localization via the 3'UTR of alpha-MyHC mRNA leading to local protein synthesis. We expect to find that the direction of mechanical strain influences the direction of growth of the muscle cell with the longitudinal strain producing mRNA localization at the ends of the cells while transverse stain produces inter-myofibrillar localization. We expect that this spatial distribution is governed by the 3'UTR. Control of cell remodeling is important for increasing the mechanical output of the heart that can be a healthy response in exercise or pathological in heart failure.
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