Latent enhancers - a novel mechanism for pain chronification?

我们都可能知道有人患有慢性疼痛——这是一种非常常见的疾病，可能是由运动损伤、各种疾病和衰老过程引起的。治疗选择是有限的，医生通常只能用止痛药来部分缓解疼痛，让他们的病人只能忍受痛苦。虽然慢性疼痛可能有许多不同的原因，但结果往往是相同的：过度敏感的神经系统比正常情况下反应更强烈。然而，一个问题仍然存在，为什么神经系统在很长一段时间内保持这种敏感状态，特别是在潜在的伤害或疾病已经消失的情况下。这项拨款旨在调查这一悖论。这是基于这样的发现：神经损伤可以改变免疫细胞中某些基因的表观遗传标记，而这些基因对持续疼痛的产生很重要。表观遗传学是决定哪个基因在哪里表达的过程。一些表观遗传信号具有直接的功能后果，而其他信号只是引物：表明潜在的行为或被修改的标志。这项拨款旨在进一步研究这一现象：我们想知道慢性疼痛状态是否不仅会改变免疫细胞中的表观遗传标记，还会改变神经元中的表观遗传标记，我们想调查这些改变的功能后果。我们的总体假设是，我们一生中遇到的许多小伤害——孤立地看是无害的——可能会留下过多的分子“足迹”，这些“足迹”可能会造成更持久的伤害，最终导致慢性疼痛。

All of us are likely to know someone that suffers from chronic pain - it is a very common condition, which can be caused by sports injuries, various diseases and the process of ageing. Treatment options are limited, and doctors are often unable to offer anything more than partial relief with a prescription of painkillers, leaving their patients resigned to suffering.While chronic pain can have many different causes, the outcome is often the same: an overly sensitive nervous system which responds much more than it normally would. However, a question still remains as to why the nervous system should remain in this sensitive state over long periods of time, especially in instances where the underlying injury or disease has gone.This grant seeks to investigate this paradox. It is based on findings that nerve damage can change epigenetic marks on some of the genes in immune cells that are known to be important for the generation of persistent pain. Epigenetics is the process that determines which gene is expressed and where. Some epigenetic signals have direct functional consequences, while others are just primers: flags that indicate a potential to act or be modified. This grant is designed to investigate this phenomenon further: we would like to find out whether a chronic pain state alters epigenetic marks not only in immune cells, but also in neurons, and we would like to investigate the functional consequences of these alterations. Our overall hypothesis is that the many small injuries we encounter over our lifetimes - innocuous in isolation - might leave a plethora of molecular 'footprints', which can add up to more lasting damage, and ultimately chronic pain.