Delineating the cell intrinsic mechanisms of peripheral nerve regeneration

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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.