Signal Integration and Protein Degradation in Muscle

肌肉中的信号整合和蛋白质降解

• 批准号: 0918031
• 负责人: Lewis Jacobson
• 金额: $ 13.06万
• 依托单位: University of Pittsburgh
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0918031&HistoricalAwards=false
• 关键词: Signal; Integration; Protein; Degradation; Muscle

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.

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肉内信号和信号转导网络。这个项目的重点是了解复杂信号网络的基本结构和行为，以便更深入地了解复杂的信号网络和信号转导路径是如何协调以调节目标组织中的蛋白质稳定性的。它将确定信号转导途径的组成部分的身份，并确定每个组成部分的数量和/或活性是否受到调节，以便绘制各组成部分之间的相互作用图。本项目强调识别反馈环路，这对网络行为至关重要。对于网络动力学的计算建模来说，这些信息(对于肌肉细胞来说还没有在这种详细程度上解决)是必不可少的。以往的研究表明，肌肉中的蛋白质降解对多种信号做出反应，并受到多种蛋白质降解机制的调节，蛋白质降解的状态取决于相反信号之间的平衡，而不是单一信号的强度。这些收敛的信号显然是通过控制Raf激酶分子的磷酸化状态来整合的。这种蛋白可以在多个特定位点(S)被磷酸化，从而组合确定Raf的产量。这一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起到“信号整合子”的正或负调节作用。本项目旨在阐明Raf如何在横纹肌的特定环境中扮演“信号整合者”的角色，特别是在蛋白质磷酸酶和钙信号的功能方面。更广泛的影响：。本科生研究人员将是项目团队不可或缺的一部分。一名研究生将接受该项目的培训。高级科学人员将作出巨大努力，将线虫生物学和神经肌肉生物学的一般方面纳入他们教授的本科课程(遗传学、生物学入门)和其他本科课程(发育生物学、细胞生物学)。使用线虫作为胰岛素信号和脂肪代谢模型的模块将被纳入高中教师研讨会，使用线虫进行基本遗传学概念探究式学习的模块将通过NIH支持的科学教育伙伴奖在K-12学校访问中提供。