Latent enhancers - a novel mechanism for pain chronification?

潜在增强剂——疼痛慢性化的新机制？

• 批准号: MR/P010814/1
• 负责人: Franziska Denk
• 金额: $ 57.07万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP010814%2F1
• 关键词: Latent; enhancers; novel; mechanism; pain

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.

我们所有人都可能认识患有慢性疼痛的人 - 这是一种非常常见的疾病，可能由运动损伤、各种疾病和衰老过程引起。治疗选择有限，医生往往只能开出止痛药来部分缓解疼痛，让患者只能忍受痛苦。虽然慢性疼痛可能有多种不同的原因，但结果往往是相同的：过度敏感的神经系统的反应比正常情况下要强得多。然而，仍然存在一个问题，即为什么神经系统应该长时间保持这种敏感状态，特别是在潜在的损伤或疾病已经消失的情况下。这项资助旨在调查这一悖论。它基于这样的发现：神经损伤可以改变免疫细胞中一些基因的表观遗传标记，这些基因已知对持续性疼痛的产生很重要。表观遗传学是决定哪个基因在何处表达的过程。一些表观遗传信号具有直接的功能后果，而另一些只是引物：表明有可能发挥作用或被修改的标志。这笔资助旨在进一步研究这一现象：我们想查明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，并且我们希望研究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（单独来看是无害的）可能会留下过多的分子“足迹”，这可能会造成更持久的损害，并最终导致慢性疼痛。

项目成果

A transcriptional toolbox for exploring peripheral neuro-immune interactions

用于探索外周神经免疫相互作用的转录工具箱

• DOI: 10.1101/813980
• 发表时间: 2019
• 作者: Liang Z

Fibroblasts: the neglected cell type in peripheral sensitisation and chronic pain? A review based on a systematic search of the literature.

• DOI: 10.1136/bmjos-2021-100235
• 发表时间: 2022
• 期刊: BMJ open science
• 作者: Shinotsuka N;Denk F
• 通讯作者: Denk F

Changes in the transcriptional fingerprint of satellite glial cells following peripheral nerve injury

• DOI: 10.1002/glia.23785
• 发表时间: 2020-02-11
• 期刊: GLIA
• 影响因子: 6.2
• 作者: Jager, Sara E.;Pallesen, Lone T.;Vaegter, Christian B.
• 通讯作者: Vaegter, Christian B.

Probing the peripheral immune response in mouse models of oxaliplatin-induced peripheral neuropathy highlights their limited translatability.

• DOI: 10.12688/wellcomeopenres.16635.2
• 发表时间: 2021
• 期刊: Wellcome open research
• 作者: Hore ZL;Villa-Hernandez S;Denk F
• 通讯作者: Denk F

TRPC5 and the path towards analgesic drug development.

TRPC5 和镇痛药物开发之路。

• DOI: 10.1016/j.tins.2021.06.010
• 发表时间: 2021
• 期刊: Trends in neurosciences
• 影响因子: 15.9
• 作者: Denk F