Mechanical activity and regional protein synthesis

(根据申请者的摘要改编)长期研究目标是了解横纹肌如何适应变化的生理需求。这个项目探索机械功、细胞内信号和蛋白质合成的局部控制之间的联系。总体假设是，机械应变是控制翻译和局部蛋白质合成的主要生理信号。具体目的1.阐明机械负荷如何通过调节α-肌球蛋白重链(MyHC)3‘端非编码区与mRNA结合蛋白之间的相互作用来调节翻译。研究人员希望发现，特定信使核核结合因子(MBF)复合体的机械活性磷酸化调节它们与α-MyHc 3‘UTR上特定顺式序列的结合，从而控制翻译。具体目的2.证明机械负荷通过α-MyHC基因3‘端非编码区调节定位，导致局部蛋白质合成。研究人员希望发现，机械应变的方向影响肌肉细胞的生长方向，纵向应变在细胞末端产生mRNA局部化，而横向应变产生肌原纤维间局部化。他们预计，这种空间分布受3‘UTR的支配。控制细胞重塑对于增加心脏的机械输出很重要，这可能是运动中的健康反应，也可能是心力衰竭的病理反应。

(Adapted from the Applicant's Abstract) The 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- myosin heavy chain (MyHC) mRNA and mRNA binding proteins. The investigators expect to find that mechanical activity phosphorylation of specific messenger ribonuclear binding factor (mBF) complexes modulate 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. The investigators 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 strain producers inter-myofibrillar localization. They 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.