Endoplasmic reticulum, Protrudin and Axon Regeneration

内质网、Protrudin 和轴突再生

• 批准号: MR/V002694/1
• 负责人: James Fawcett
• 金额: $ 108.4万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV002694%2F1
• 关键词: Endoplasmic; reticulum; Protrudin; Axon; Regeneration

The aim of the application is to develop new methods to stimulate regeneration of nerve fibres in the injured spinal cord and optic nerve. At present when the spinal cord or optic nerve are damaged the nerve fibres are unable to regenerate and little function can be restored. There has been a steady increase in our understanding of why nerve fibre regeneration fails, and treatments have been developed that stimulate regeneration, although not sufficiently to make a successful treatment for patients. This application aims to develop new methods to increase the intrinsic regeneration potential of neurons that connect to the spinal cord and connect the eye to the brain, whilst increasing our understanding of the mechanisms that control regeneration in the adult central nervous system.The current application focuses on the endoplasmic reticulum (ER). This is the largest organelle in cells, and has branches that travel down the length of nerve fibres. We believe that changes in the ER may be one of the main reasons that nerve fibres in the brain and spinal cord lose the ability to regenerate as they mature. This hypothesis came from our work with the molecule protrudin, which we have found to the be the strongest promoter of regeneration that we have seen. Protrudin is an adaptor molecule that brings together several molecules and structures that are needed for regeneration. Importantly, it attaches to the ER and drags it to the tip of nerve fibres. We find that ER diminishes in nerve fibres as they mature and lose the ability to regenerate, but protrudin restores the ER to nerve fibre tips and growth cones. If the ER-binding of protrudin is removed, it no longer promotes regeneration. The grant focuses on the role of the ER in regeneration. The ER has many functions that should be essential for good regeneration, but it has not been studied in this context. The experiments will study the anatomy of the ER and its enzymes in nerve fibres that regenerate vigorously versus those that have matured and lost the ability to regenerate. There are many molecules that affect the distribution and anatomy of ER, and a selection of these will be used to increase and decrease ER in the different types of nerve fibre. Also some of the key functions of the ER will be manipulated. Together, these experiments should give conclusive proof of whether the ER is a key player in regeneration. The treatments that have been successful in promoting regeneration in tissue culture experiments will then be tested for their ability to promote regeneration in the optic nerve and spinal cord.

该申请的目的是开发新的方法来刺激受损脊髓和视神经中神经纤维的再生。目前，当脊髓或视神经受损时，神经纤维不能再生，几乎不能恢复功能。我们对神经纤维再生失败的原因的理解稳步增加，并且已经开发出刺激再生的治疗方法，尽管不足以为患者提供成功的治疗。本申请旨在开发新的方法来增加连接到脊髓和连接眼睛到大脑的神经元的内在再生潜力，同时增加我们对控制成人中枢神经系统再生的机制的理解。目前的应用重点是内质网（ER）。这是细胞中最大的细胞器，并且具有沿着神经纤维长度行进的分支。我们认为，ER的变化可能是大脑和脊髓中的神经纤维在成熟时失去再生能力的主要原因之一。这个假设来自于我们对分子Escheridin的研究，我们发现它是我们所见过的最强的再生启动子。Protrudin是一种衔接分子，它将再生所需的几种分子和结构结合在一起。重要的是，它附着在ER上并将其拖到神经纤维的尖端。我们发现ER在神经纤维中随着它们的成熟而减少并失去再生能力，但Escheridin将ER恢复到神经纤维尖端和生长锥。如果ER结合的Escheridin被删除，它不再促进再生。赠款的重点是ER在再生中的作用。ER具有许多功能，这些功能对于良好的再生至关重要，但尚未在此背景下进行研究。这些实验将研究ER及其酶在神经纤维中的解剖结构，这些神经纤维再生旺盛，而不是那些已经成熟并失去再生能力的神经纤维。有许多分子影响ER的分布和解剖结构，并且这些分子的选择将用于增加和减少不同类型神经纤维中的ER。ER的一些关键功能也将被操纵。总之，这些实验应该提供确凿的证据，证明ER是否是再生的关键参与者。然后将测试在组织培养实验中成功促进再生的治疗方法促进视神经和脊髓再生的能力。

项目成果

The extracellular matrix and perineuronal nets in memory.

记忆中的细胞外基质和神经周围网。

• DOI: 10.17863/cam.84384
• 发表时间: 2022
• 作者: Fawcett J

Regenerative capacity of neural tissue scales with changes in tissue mechanics post injury

神经组织的再生能力随损伤后组织力学的变化而变化

• DOI: 10.1101/2022.12.12.517822
• 发表时间: 2022
• 作者: Carnicer-Lombarte A

Integrin-Driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program.

• DOI: 10.1523/jneurosci.2076-22.2023
• 发表时间: 2023-06-28
• 期刊: JOURNAL OF NEUROSCIENCE
• 影响因子: 5.3
• 作者: Cheah, Menghon;Cheng, Yuyan;Petrova, Veselina;Cimpean, Anda;Jendelova, Pavla;Swarup, Vivek;Woolf, Clifford J.;Geschwind, Daniel H.;Fawcett, James W.
• 通讯作者: Fawcett, James W.

Quantifying inter-organelle membrane contact sites using proximity ligation assay in fixed optic nerve sections.

使用固定视神经截面中的接近连接测定法量化轨道间膜接触位点。

• DOI: 10.1016/j.exer.2021.108793
• 发表时间: 2021-12
• 期刊: Experimental eye research
• 影响因子: 3.4
• 作者: Ching J;Osborne A;Eva R;Prudent J;Yu-Wai-Man P
• 通讯作者: Yu-Wai-Man P

Integrin-driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program

整合素驱动的脊髓轴突再生激活了独特的中枢神经系统再生程序

• DOI: 10.1101/2021.12.07.471602
• 发表时间: 2021
• 作者: Cheah M