Inhibition of reverse transcription in type I interferon mediated neuropathology

I 型干扰素介导的神经病理学中逆转录的抑制

• 批准号: MR/S034676/1
• 负责人: Yanick Crow
• 金额: $ 219.09万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS034676%2F1
• 关键词: Inhibition; reverse; transcription; type; interferon

Aicardi-Goutières syndrome (AGS) is a severe childhood disease of the brain associated with very high levels of a chemical called type I interferon. Normally, we only produce interferon when we are infected with a virus. In AGS, there is no obvious viral infection. Instead, due to changes (mutations) in the genetic code (contained in our 'DNA') in these individuals, we believe that the cells in the body are fooled into thinking that the person's own DNA is viral - that is to say, there is a confusion in telling 'self' from 'non-self'. In fact, a large amount of our own DNA is made up of ancient virus ('endogenous retrovirus'), that we have taken into our genetic material over millions of years - sometimes referred to as 'junk' DNA. These endogenous retroviruses can still act like a virus coming from outside of the body, so that they need to be controlled. We have wondered if the genetic changes causing AGS mean that these normal control mechanisms don't work. If that was true, the endogenous retroviruses would start to make copies of themselves which could be recognised by our immune system as 'foreign', leading to the continuous production of interferon which then damages the cells in our body. Since we cannot repair the genetic code in every cell, we wish to treat AGS patients with drugs called reverse transcriptase inhibitors (RTIs). RTIs are used to fight the HIV-1 virus that causes AIDS. In the case of AGS, we are not treating HIV-1, but we wonder if the same drugs might be able to control endogenous retroviruses that we think are driving interferon production. Indeed, using this treatment in a recently completed study we gathered early information to suggest that we did see a reduction in interferon levels in patients over a one year period, with levels of interferon increasing when we stopped the drugs. Additionally, from a scientific point of view, these studies are of great potential importance for patients with AGS and their families. Scientifically, our project will be of considerable interest if the results support the possibility that junk DNA can sometimes be associated with human disease. RTIs are very safe drugs, that have been used in millions of people with HIV-1 around the world. If our results turn out to be convincing, we believe that it might also be worth thinking about treating other diseases that have also been shown to be associated with increased levels of type I interferon, including the much more common immune condition called systemic lupus erythematosus.

艾卡迪-古蒂埃综合征(AGS)是一种严重的儿童脑部疾病，与一种名为I型干扰素的化学物质水平过高有关。正常情况下，我们只有在感染病毒时才会产生干扰素。在AGS中，没有明显的病毒感染。相反，由于这些个体的遗传密码(包含在我们的‘DNA’中)的变化(突变)，我们相信体内的细胞被愚弄，以为这个人自己的DNA是病毒--也就是说，在区分‘自我’和‘非我’方面存在混淆。事实上，我们自身的大量DNA是由古老的病毒(内源性逆转录病毒)组成的，我们在数百万年的时间里把这种病毒带入了我们的遗传物质--有时被称为“垃圾”DNA。这些内源性逆转录病毒仍然可以像来自体外的病毒一样发挥作用，因此需要控制它们。我们想知道，导致AGS的基因变化是否意味着这些正常的控制机制不起作用。如果这是真的，内源性逆转录病毒将开始复制自己，这可以被我们的免疫系统识别为“外来的”，导致干扰素的持续产生，然后损害我们体内的细胞。由于我们不能修复每个细胞中的遗传密码，我们希望用逆转录酶抑制剂(RTI)来治疗AGS患者。RTI被用来对抗导致艾滋病的HIV-1病毒。在AGS的案例中，我们不是在治疗HIV-1，但我们想知道，同样的药物是否能够控制我们认为正在推动干扰素产生的内源性逆转录病毒。事实上，在最近完成的一项研究中使用这种治疗方法，我们收集了早期信息，表明在一年的时间里，我们确实看到患者的干扰素水平下降，当我们停止药物时，干扰素水平上升。此外，从科学的角度来看，这些研究对AGS患者及其家人具有很大的潜在重要性。从科学上讲，如果结果支持垃圾DNA有时与人类疾病有关的可能性，我们的项目将会引起相当大的兴趣。RTI是非常安全的药物，已经在世界各地数百万艾滋病毒携带者身上使用。如果我们的结果证明是令人信服的，我们认为也值得考虑治疗其他疾病，这些疾病也被证明与I型干扰素水平升高有关，包括更常见的称为系统性红斑狼疮的免疫疾病。

项目成果

Cellular reprogramming and epigenetic rejuvenation.

• DOI: 10.1186/s13148-021-01158-7
• 发表时间: 2021-09-06
• 期刊: Clinical epigenetics
• 影响因子: 5.7
• 作者: Simpson DJ;Olova NN;Chandra T
• 通讯作者: Chandra T

Region-based epigenetic clock design improves RRBS-based age prediction.

• DOI: 10.1111/acel.13866
• 发表时间: 2023-08
• 期刊: AGING CELL
• 影响因子: 7.8
• 作者: Simpson, Daniel J. J.;Zhao, Qian;Olova, Nelly N. N.;Dabrowski, Jan;Xie, Xiaoxiao;Latorre-Crespo, Eric;Chandra, Tamir
• 通讯作者: Chandra, Tamir

Region-Based Epigenetic Clock Design Improves RRBS-Based Age Prediction

基于区域的表观遗传时钟设计改进了基于 RRBS 的年龄预测

• DOI: 10.1101/2023.01.13.524017
• 发表时间: 2023
• 作者: Simpson D