A novel mechanism that inhibits axon regeneration

描述（由申请人提供）：轴突再生是神经元的基本和保守特性。该领域的一个关键问题是发现是什么决定了受损神经元的再生能力。该提案的首要目标是发现三种新的因子-Notch，Mint/LIN-10和Rab 6-如何抑制再生。三个中心假设是：1）Mint/LIN- 10和Rab 6在受损的神经元中共同作用以抑制再生; 2）它们通过促进一种或多种抑制因子的细胞内运输来这样做;和3）Notch信号调节这种抑制系统的一种或多种组分。这些假设得到了大量初步数据的支持，并将在三个目标中进行检验。1)定义Mint和Rab 6在运动和感觉神经元中的再生功能。这一目标将确定Mint/LIN-10和Rab 6如何共同抑制轴突再生，以及它们如何在不同的神经元中发挥作用。2)分析再生中的Mint/LIN-10结合配偶体。这一目标将确定介导Mint/LIN-10再生功能的效应分子。3)研究Mint、Rab 6和调控轴突再生的效应子的细胞生物学。该目标将使用体内真实的时间成像来确定这些抑制因子的细胞内运输和轴突再生之间的联系。这些目标使用了一些创新的技术，该提案作为一个整体提供了一个重大的概念性进展，我们的理解蛋白质功能和细胞内贩运轴突再生。通过描述一种新的神经元机制，抑制神经元损伤后再生的能力，这一建议有可能显着影响和改善目前的努力，寻找新的治疗受损轴突。

DESCRIPTION (provided by applicant): Axon regeneration is a fundamental and conserved property of neurons. A key question in the field is to discover what determines the regenerative capacity of injured neurons. The overarching goal of this proposal is to discover how three novel factors-Notch, Mint/LIN-10, and Rab6-function to inhibit regeneration. The three central hypotheses are: 1) that Mint/LIN- 10 and Rab6 work together in injured neurons to inhibit regeneration; 2) that they do so by promoting the intracellular trafficking of one or more inhibitory factors; and 3) that Notch signaling regulates one or more components of this inhibitory system. These hypotheses are supported by substantial preliminary data, and will be tested in the three Aims. 1) Define the regeneration function of Mint and Rab6 in motor and sensory neurons. This aim will establish how Mint/LIN-10 and Rab6 work together to inhibit axon regeneration, and how they function in different neurons. 2) Analyze Mint/LIN-10 binding partners in regeneration. This aim will identify the effector molecules that mediate Mint/LIN-10's regeneration function. 3) Investigate the cell biology of Mint, Rab6, and effectors in regulating axon regeneration. This aim will use in vivo real time imaging to determine the link between intracellular trafficking of these inhibitory factors and axon regeneration. These aims use a number of innovative techniques, and the proposal as a whole provides a major conceptual advance in our understanding of protein function and intracellular trafficking in relation to axon regeneration. By describing a novel neuronal mechanism that inhibits the ability of neurons to regenerate after injury, this proposal has the potential to significantly affect and improve curren efforts to find new treatments for damaged axons.