Mechanical activity and regional protein synthesis

长期研究目标是了解横纹肌如何适应其分子组成以响应改变的生理需求。该项目探索机械功，细胞内信号和蛋白质合成的局部控制之间的联系。总的假设是，机械应变是控制翻译和区域蛋白质合成的主要生理信号。具体目标1。显示机械负荷如何通过调节α-肌球蛋白重链（MyHC）mRNA的3 'UTR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，特定信使核糖核结合因子（mBF）复合物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。具体目标2。表明机械负荷通过α-MyHC mRNA的3 'UTR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细胞的生长方向，纵向应变产生细胞末端的mRNA定位，而横向应变产生肌原纤维间的定位。他们认为这种空间分布受3 'UTR的控制。控制细胞重塑对于增加心脏的机械输出是重要的，这可以是运动中的健康反应或心力衰竭中的病理反应。

(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.