Endoplasmic reticulum, Protrudin and Axon Regeneration

该应用的目的是开发新的方法来刺激损伤的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，神经纤维无法再生，功能几乎不能恢复。我们对神经纤维再生失败的原因的了解稳步增加，已经开发出刺激再生的治疗方法，尽管还不足以使患者获得成功的治疗。这一应用旨在开发新的方法来增加连接到脊髓和连接眼睛和大脑的神经元的内在再生潜力，同时增加我们对成人中枢神经系统再生控制机制的了解。目前的应用集中在内质网(ER)。这是细胞中最大的细胞器，有沿神经纤维延伸的分支。我们认为，内质网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。这一假说来自我们对前突蛋白分子的研究，我们发现它是我们所见过的最强的再生促进剂。Protrudin是一种适配器分子，它将再生所需的几个分子和结构聚集在一起。重要的是，它附着在内质网上，并将其拖到神经纤维的末端。我们发现，随着神经纤维的成熟和再生能力的丧失，内质网减少，但突起蛋白将内质网恢复到神经纤维尖和生长锥体。如果前突蛋白的内质网结合被移除，它不再促进再生。这笔赠款的重点是ER在再生中的作用。内质网有许多功能，对于良好的再生应该是必不可少的，但它还没有在这个背景下进行研究。这些实验将研究神经纤维中内质网及其酶的解剖学，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。有许多分子影响内质网的分布和解剖，其中一些分子将用于增加和减少不同类型神经纤维中的内质网。此外，ER的一些关键功能也将被操纵。总而言之，这些实验应该会给出确凿的证据，证明内质网是否是再生的关键参与者。在组织培养实验中成功促进再生的治疗方法将被测试其促进视神经和脊髓再生的能力。

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.