Delineating the cell intrinsic mechanisms of peripheral nerve regeneration

外周神经系统将来自大脑和脊髓的信号连接到我们的皮肤和肌肉，允许我们移动、感觉和感觉我们的周围环境。当这些神经受损时，这些功能会受到干扰，患者通常需要手术修复受损的神经。与大脑和脊髓的中枢神经系统中的神经不同，周围神经在受伤后能够再生。不幸的是，这永远不足以为患者提供完全康复，因为再生过程非常缓慢和不稳定。修复神经的手术可以帮助恢复，但这些手术60多年来一直没有改变，仍然没有完全恢复。这给患者留下了身体和情感上的损伤。了解周围神经如何能够自我修复是开发治疗神经损伤的新方法的关键。这项研究项目将集中在损伤后组成我们周围神经的单个细胞内发生了什么。这将在周围神经损伤的大鼠模型上进行。我将使用附着在细胞内蛋白质上的荧光标记来照亮特定的结构，这些结构可能涉及协调神经再生的过程。这将与使用最先进的显微镜相结合，后者能够在细胞再生时拍摄高分辨率视频。这将让我们了解损伤后神经再生的过程以及为什么会出错。细胞内有一些特定的结构，被认为在允许周围神经再生并最终重新连接到它们向其发送电信号的皮肤和肌肉方面非常重要。其中一个结构被称为高尔基体，通常用于将蛋白质从神经的一端输送到另一端，使其正常工作。高尔基体的另一个功能被认为是在受伤后重塑细胞骨架，允许连接脊髓与皮肤和肌肉(称为轴突)的非常长的伸展部分再生。我将阐明这个结构，并找出它在细胞内的形状和位置在再生过程中是否发生变化。通过改变细胞的遗传密码和扰乱高尔基体的功能，我将能够确定神经再生是否需要这种结构。如果需要高尔基器械，这可能是非常重要的，因为我们可能能够开发出针对这种结构的神经损伤的新疗法。众所周知，如果修复受损神经的手术被推迟，可能会导致患者恢复较差，但原因尚不完全清楚。如果神经修复得更快，高尔基体对“损伤信号”的反应可能会更快。为了测试这一点，我将使用我的周围神经损伤的大鼠模型。这种损伤的修复将立即进行，一周后或两个月后。然后，我将拍摄神经的荧光图像，以评估神经再生的程度，以及高尔基体的结构和位置。再一次，我将改变神经内细胞的遗传密码，扰乱高尔基体的功能。预计这将导致无序的神经再生。所有这些实验的目的都是找出我们神经细胞内的哪些结构可能允许再生发生。我们认为高尔基仪器可能很重要，并将专注于此。找出是什么让神经再生，以及为什么需要早期手术修复，这一点很重要，原因有两个：1)当考虑为神经损伤患者进行新的治疗时，它将使神经细胞中的特定结构成为目标。2.)它可能会告诉我们为什么大脑和脊髓中的神经不能再生，以及我们如何克服这一点。

The peripheral nervous system connects the signals from the brain and spinal cord to our skin and muscles, allowing us to move, feel and sense our surroundings. When these nerves are injured these functions are disturbed and patients usually need surgery to repair the damaged nerves. Unlike the nerves in the central nervous system of the brain and spinal cord, peripheral nerves are able to regrow after injury. Unfortunately this is never enough to provide full recovery for the patients as the regrowth process is very slow and unstable. Surgery to repair the nerves can help with recovery but these operations have remained unchanged for over 60 years and still do not lead to a complete recovery. This leaves patients with both physical and emotional impairment. Understanding how the peripheral nerves are able to self-repair is key to developing new methods of treating nerve injuries.This research project will focus on what happens inside the individual cells that make up our peripheral nerves after injury. This will be carried out in a rat model of peripheral nerve injury. I will use fluorescent markers which attach to the proteins inside the cells to illuminate specific structures which may be involved in coordinating the process of nerve regrowth. This will be combined with the use of state of the art microscopes which are able to take high-resolution videos of the cells whilst they regrow. This will give us an understanding of what the process of nerve regrowth after injury looks like and also why it might go wrong.There are some specific structures inside cells which are thought to be very important in allowing peripheral nerves to regrow and ultimately reconnect to the skin and muscle that they send electrical signals to. One of these structures is called the Golgi apparatus and this usually is used for carrying proteins from one end of the nerve to the other, allowing it to function properly. Another function for the Golgi apparatus is thought to be in reforming the skeleton of the cell after injury, allowing the very long extension that connects the spinal cord to the skin and muscles (known as the axon) to regrow. I will illuminate this structure and find out whether its shape and position within the cells changes during the process of regrowth. By changing the genetic code of the cells and disrupting the function of the Golgi apparatus I will be able to determine whether this structure is needed for nerves to regrow. If the Golgi apparatus is needed, this could be very important as we may be able to develop new treatments for nerve injury which can target this structure.It is known that if surgery to repair injured nerves is delayed, this can lead to poorer recovery for patients but it is not fully known why this is the case. It could be that the Golgi apparatus responds to the 'injury signals' quicker if the nerve in repaired faster. In order to test this I will use my rat model of peripheral nerve injury. Repair of this injury will be carried out immediately, after one week or after two months. I will then take fluorescent images of the nerve to assess how much the nerve has regrown and also what the structure and position of the Golgi apparatus is. Again, I will alter the genetic code of the cells within the nerve and disrupt the function of the Golgi apparatus. It is expected that this will lead to disordered nerve regrowth.All of these experiments aim to find out which structures inside our nerve cells might allow for regrowth to occur. We think that the Golgi apparatus may be important and will focus on this. Finding out what makes nerves regrow and also why early surgical repair is needed will be important for two reasons: 1.) it will enable specific structures in nerve cells to be targeted when thinking about making new treatments for patients with nerve injuries. 2.) It may tell us why nerves in the brain and spinal cord are not able to regenerate and how we might overcome this.