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的特性。该领域的一个关键问题是发现是什么决定了受伤神经元的再生能力。本提案的总体目标是发现notch、Mint/LIN-10和rab6这三种新因子如何抑制再生。三个主要假设是：1)Mint/LIN- 10和Rab6在损伤神经元中共同抑制再生；2)它们通过促进一种或多种抑制因子的细胞内运输来实现；3) Notch信号调节该抑制系统的一个或多个组分。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验证：1)定义Mint和Rab6在运动和感觉神经元中的再生功能。本研究旨在确定Mint/LIN-10和Rab6如何共同抑制轴突再生，以及它们在不同神经元中的作用。2)分析Mint/LIN-10在再生中的结合伙伴。本研究旨在鉴定介导Mint/LIN-10再生功能的效应分子。3)研究Mint、Rab6及其效应物对轴突再生的调控作用。该目标将使用体内实时成像来确定这些抑制因子的细胞内运输与轴突再生之间的联系。这些目标使用了许多创新的技术，总的来说，这个建议为我们理解与轴突再生有关的蛋白质功能和细胞内运输提供了一个重要的概念上的进步。通过描述一种抑制损伤后神经元再生能力的新神经元机制，这一提议有可能显著影响和改善目前寻找受损轴突新治疗方法的努力。

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.