Signal Integration and Protein Degradation in Muscle

该奖项是根据2009年美国复苏和再投资法案（公法111-5）资助的，该项目的长期目标是了解调节肌肉中蛋白质降解的外部和肌内信号以及信号转导网络。该项目的重点是了解复杂信号网络的基本结构和行为，以更深入地了解复杂的信号和信号转导通路网络如何协调以调节靶组织中的蛋白质稳定性。它将建立信号转导途径的组件的身份，并确定每个组件的量和/或活性是否受到调节，以映射组件之间的相互作用。该项目强调对网络行为至关重要的反馈回路的识别。这些信息（尚未在肌肉细胞的这种细节水平上得到解决）对于网络动力学的计算建模是必不可少的。以往的研究表明，肌肉中的蛋白质降解响应于多种信号，并由多种蛋白水解机制介导，并且蛋白质降解的状态由相反信号之间的平衡而不是单个信号的强度决定。这些会聚信号显然是通过控制Raf激酶分子的磷酸化状态来整合的。这种蛋白质可以在多个特定位点磷酸化，因此Raf的输出是组合确定的。这种机制的一个重要结果是，作用于Raf上特定位点的磷酸酶可能作为“信号整合剂”的正或负调节剂。该项目旨在阐明Raf如何在横纹肌的特定背景下作为“信号整合器”，特别是在蛋白磷酸酶和钙信号传导的功能方面。 更广泛的影响：本科研究人员将成为项目团队的一个组成部分。一名研究生将接受该项目的培训。高级科学人员将作出强有力的努力，将C。线虫生物学和神经肌肉生物学一般纳入本科课程，他们教（荣誉课程遗传学，生物学导论）和其他本科课程（发育生物学，细胞生物学）。使用C. elegans作为胰岛素信号和脂质代谢的模型被纳入高中教师的研讨会和使用C.用于基本遗传学概念的探究式学习的优雅将通过NIH支持的科学教育合作奖在K-12学校访问中提供。

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5) The long-range objective of this project is to understand the external and intramuscular signals and signal-transduction networks that regulate protein degradation in muscle. This project focuses on understanding the basic architecture and behavior of a complex signaling network to provide a closer understanding of how complex networks of signals and signal-transduction pathways are coordinated to regulate protein stability in the target tissue. It will establish the identities of the components of the signal-transduction pathways and determine whether the amount and/or the activity of each component is regulated, in order to map the interplay among components. This project emphasizes the identification of feedback loops, which are crucial to network behavior. This information (which has not yet been worked out at this level of detail for muscle cells) is indispensable for computational modeling of network dynamics. Previous studies have made it clear that protein degradation in muscle responds to multiple signals and is mediated by multiple proteolytic mechanisms, and that the state of protein breakdown is determined by the balance among opposing signals rather than the intensity of a single signal. These convergent signals are apparently integrated by control of the phosphorylation state of the Raf kinase molecule. This protein can be phosphorylated at multiple specific site(s) and the output of Raf is thus determined combinatorially. An important consequence of this mechanism is that the phosphatases that act on specific sites on Raf may act as positive or negative regulators of the "signal integrator". This project aims to elucidate how Raf acts as a "signal integrator" in the specific context of striated muscle, particularly in terms of the functions of protein phosphatases and of calcium signaling. Broader impacts:. Undergraduate researchers will be an integral part of the project team. One graduate student will be trained on the project. The senior scientific personnel will make strong efforts to incorporate aspects of C. elegans biology and neuromuscular biology in general into undergraduate courses they teach (Honors courses in Genetics, Introductory Biology) and into other undergraduate courses (Developmental Biology, Cell Biology). Modules using C. elegans as a model for insulin signaling and lipid metabolism are incorporated into workshops for high-school teachers and a module using C. elegans for inquiry-based learning of basic genetics concepts will be delivered in K-12 school visits through an NIH-supported Science Education Partnership Award.