Targeting circadian mechanism for novel chronic pain treatments

慢性疼痛是社会的一个巨大负担。治疗方法还不够好，很难开发出来。感觉信息，如触摸和疼痛，由被称为外周感觉神经元的特殊神经携带。我们有强大的内在机制来调节我们对疼痛的感知。这包括存在于我们体内的时钟，它帮助我们与24小时昼夜循环保持一致。众所周知，在一天中的特定时间，许多疼痛状况会恶化或改善。了解为什么疼痛会以这种方式发作并稳定下来，可能会为治疗和管理慢性疼痛提供新的方法。它还可能帮助患者了解他们的疼痛状况可能恶化的时间，然后制定更好的应对策略，并允许更好的医疗疼痛治疗时机。我们在老鼠身上发现，包括疼痛神经在内的外周神经有一个内在的时钟。我们现在打算研究人类外周感觉神经的时钟。这是通过一种名为诱导多能干细胞(IPSC)的技术实现的。IPSC是通过提取一个人的血液或皮肤细胞，并通过激活特定基因将其转化为干细胞而形成的。然后，通过在特定条件下培养干细胞，它们可以转化为疼痛神经细胞。在这个项目中，我们还能够从最近去世并同意捐赠器官的人那里获得疼痛神经。我们将使用IPSC-疼痛神经和来自器官捐赠者的人类疼痛神经来检查时钟。我们将研究时钟如何改变疼痛神经的功能方式--例如，在一天中的特定时间变得更加兴奋。我们发现的机制可能对遭受慢性疼痛的人很重要。我们将首先研究人类疼痛神经细胞的哪些特性是由内部时钟决定的。然后我们将研究在这一过程中可能重要的分子。对神经最重要的分子之一是离子通道。这些细胞允许钠和钾等盐进入和离开细胞。神经使用离子通道来设置它们的兴奋性，并发送信号。我们认为时钟正在调节离子通道的行为方式。通过详细探讨这一点，我们相信我们可以找到治疗疼痛的新方法。

Chronic pain is a huge burden for society. Treatments are not good enough and difficult to develop. Sensory information, such as touch and pain, is carried by specialised nerves called peripheral sensory neurons. We have powerful in-built mechanisms for regulating our perception of pain. This includes clocks present in our body which helps us align to the 24 hour day and night cycle. It is quite well know that many pain conditions worsen or improve at particular times of the day. Understanding why pain can flare up and settle down in this way might offer new ways to treat and manage chronic pain. It may also help patients understand when their pain condition is likely to exacerbate and to then develop better coping strategies and allow better timing of medical pain treatments. We have discovered in mice that peripheral nerves, including pain nerves, have an internal clock. We now intend to investigate the clock in human peripheral sensory nerves. This is possible through a technology called induced pluripotent stem cells (iPSC). iPSC are made by taking a person's blood or skin cell and turning it into a stem cell by activating specific genes. Thenm by growing the stem cells in particular conditions, they can be turned into pain nerve cells. In this project we are also able to obtain pain nerves from people who have recently died and agreed to donate their organs. We will use iPSC-pain nerves and human pain nerves from organ donors to examine the clock. We will investigate how the clock can change the way in which pain nerves function - being more excitable for example at particular times of the day. The mechanisms we discovery may be important for people suffering chronic pain. We will first investigate in human pain nerve cells which properties are determined by the internal clock. We will then examine the molecules that may be important in this process. One of the most important type of molecules for nerves are called ion channels. These allow salts such as sodium and potassium to cross in and out of the cell. Nerves use ion channels to set how excitable they are and to send signals. We think the clock is regulating the way in which ion channels are behaving. By exploring this in detail, we believe we can find new ways to treat pain.