JPND: Targeting epigenetic dysregulation in the brainstem in Alzheimer's Disease (EPI-AD)

JPND：针对阿尔茨海默病脑干的表观遗传失调 (EPI-AD)

基本信息

批准号：
MR/N027973/1
负责人：
Katie Lunnon
金额：
$ 34.15万
依托单位：
UNIVERSITY OF EXETER
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FN027973%2F1
关键词：
JPND Targeting epigenetic dysregulation brainstem

项目摘要

Alzheimer's disease is a very complex disease, with its cause still largely unknown, although it is widely believed that both genetic and environmental factors can alter a person's risk. In 2015 more than 850,000 people will be living with dementia in the UK, with care costs in excess of £26 billion per year. Alzheimer's disease accounts for more than 60% of dementia cases and is characterised by the loss of specific brain cells, leading to increasingly severe behavioural and personality changes, loss of the sufferer's independence, ever greater care requirements and ultimately death after many unfortunate years of suffering. Curiously the disease is characterised by brain cell loss in only some areas of the brain with some regions affected very early in disease, particularly areas of the brain involved in learning and memory, whilst other regions are relatively resistant to nerve cell loss. Although much progress has been made in understanding the cellular changes that happen in the brain in Alzheimer's disease, the treatments currently available only temporarily improve symptoms and do not treat the underlying disease. This is because by the time a person starts displaying symptoms of the disease, such as forgetfulness and personality changes, the "hallmarks" of Alzheimer's disease, which include nerve cell loss, amyloid plaque deposition and tangle formation, have already started in the brain. In fact some recent studies have shown that these changes may have been in the brain for up to ten years prior to diagnosis. Four key pivotal questions must be answered before a truly effective treatment for Alzheimer's disease can be developed. First we need to understand why the disease affects certain individuals, whilst other people remain cognitively healthy, even into very old age. Second we need to understand why certain regions of the brain succumb to disease, whilst others seem to be far less susceptible. Third we need to identify new markers of disease, called "biomarkers" that are easy to measure in blood, and that are able to not just diagnose the disease early, but to also predict how quickly a person will develop symptoms. Finally, we need to identify new drug targets. This project plans to combine clinical, genetic and molecular data to better understand the causes of Alzheimer's disease. It is known that the expression of genes and the production of proteins relies not only on a person's specific DNA code (their genome), but can also be altered by an extra level of information called the "epigenome". Epigenetic processes are essentially chemical tags that are added to the DNA, and act to turn genes on and off, without changing the DNA sequence, and can be influenced by external factors such as the environment in which cells or individuals dwell. This project will look at levels of two different chemical tags (DNA methylation and hydroxymethylation) in the brainstem of people with Alzheimer's disease to identify genes that are epigenetically altered in disease, and could thus represent novel pharmacological targets for intervention. Further, we will look at levels of the DNA methylation tag in genes in blood samples from people with mild cognitive impairment, who represent a group of individuals at risk of developing Alzheimer's disease, to enable us to identify predictive biomarkers to allow early diagnosis. Finally we will attempt to model our epigenetic changes in an advanced experimental model system for Alzheimer's disease using induced Pluripotent Stem Cells (iPSCs) derived from the blood of Alzheimer's disease patients and age-matched controls.

阿尔茨海默氏病是一种非常复杂的疾病，其病因仍然很大程度上未知，但人们普遍认为遗传和环境因素都会改变一个人的风险。2015 年，英国将有超过 850,000 人患有痴呆症，并需要支付护理费用。每年超过 260 亿英镑的阿尔茨海默病占痴呆症病例的 60% 以上，其特点是特定脑细胞的丧失，导致日益严重的行为和性格变化、丧失能力。患者的独立性、越来越多的护理需求以及在多年不幸的痛苦后最终死亡。奇怪的是，这种疾病的特点是仅大脑某些区域的脑细胞丧失，某些区域在疾病早期就受到影响，特别是涉及学习的大脑区域。和记忆，而其他区域相对抵抗神经细胞损失，尽管在了解阿尔茨海默病大脑中发生的细胞变化方面已经取得了很大进展，但目前可用的治疗只能暂时改善症状，并不能治疗潜在的疾病。这是因为当一个人开始阿尔茨海默病的“标志”包括神经细胞损失、淀粉样蛋白斑沉积和缠结形成，这些症状已经在大脑中开始出现，例如健忘和性格改变。在开发出真正有效的阿尔茨海默病治疗方法之前，大脑中可能已经存在了长达十年的变化。首先，我们需要了解为什么这种疾病会影响某些人，而另一些人则会受到影响。保持认知健康，甚至其次，我们需要了解为什么大脑的某些区域会罹患疾病，而其他区域似乎不易患病。第三，我们需要确定新的疾病标记，称为“生物标记”，可以在血液中轻松测量。，不仅能够早期诊断疾病，还能预测一个人出现症状的速度。最后，该项目计划结合临床遗传和分子数据，以更好地了解该疾病。众所周知，阿尔茨海默病的病因。基因的表达和蛋白质的产生不仅依赖于一个人的特定 DNA 代码（基因组），而且还可以通过称为“表观基因组”的额外信息进行改变，表观遗传过程本质上是添加到基因组中的化学标签。 DNA，并在不改变 DNA 序列的情况下打开和关闭基因，并且可能受到外部因素的影响，例如细胞或个体所处的环境。该项目将研究两种不同化学标签（DNA 甲基化和 DNA 甲基化）的水平。羟甲基化）研究人员利用阿尔茨海默病患者的脑干来识别在疾病中发生表观遗传改变的基因，从而可以代表新的干预药理学目标。此外，我们将研究轻度认知障碍患者血液样本中基因的 DNA 甲基化标签水平。他们代表了一群有患阿尔茨海默病风险的个体，使我们能够识别预测生物标志物，以便进行早期诊断。最后，我们将尝试使用诱导多能干在阿尔茨海默病的先进实验模型系统中模拟我们的表观遗传变化。细胞 (iPSC) 源自阿尔茨海默病患者和年龄匹配的对照者的血液。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An epigenome-wide association study of Alzheimer's disease blood highlights robust DNA hypermethylation in the HOXB6 gene.

DOI：
10.1016/j.neurobiolaging.2020.06.023
发表时间：
2020-11
期刊：
Neurobiology of aging
影响因子：
4.2
作者：
Roubroeks JAY;Smith AR;Smith RG;Pishva E;Ibrahim Z;Sattlecker M;Hannon EJ;Kłoszewska I;Mecocci P;Soininen H;Tsolaki M;Vellas B;Wahlund LO;Aarsland D;Proitsi P;Hodges A;Lovestone S;Newhouse SJ;Dobson RJB;Mill J;van den Hove DLA;Lunnon K
通讯作者：
Lunnon K

Characterization of DNA Methylomic Signatures in Induced Pluripotent Stem Cells During Neuronal Differentiation.

DOI：
10.3389/fcell.2021.647981
发表时间：
2021
期刊：
Frontiers in cell and developmental biology
影响因子：
5.5
作者：
Imm J;Pishva E;Ali M;Kerrigan TL;Jeffries A;Burrage J;Glaab E;Cope EL;Jones KM;Allen ND;Lunnon K
通讯作者：
Lunnon K

Epigenetic dysregulation of brainstem nuclei in the pathogenesis of Alzheimer's disease: looking in the correct place at the right time?