A multi-omic approach to investigating biological mechanisms related to the aetiology and treatment of major depressive disorder.

采用多组学方法研究与重度抑郁症的病因学和治疗相关的生物学机制。

• 批准号: MR/N014863/1
• 负责人: Timothy Powell
• 金额: $ 34.67万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 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%2FN014863%2F1
• 关键词: multi; omic; approach; investigating; biological

Major depression is a brain disorder that affects 350 million people worldwide. Depressed patients experience extreme periods of low mood, loss of pleasure, problems with their appetite and difficulties sleeping. Currently, antidepressants are the first line of treatment for depression but only one third of patients respond to the first prescribed antidepressant, and one third will not respond to multiple forms of treatment. Consequently, a better understanding of what causes major depression and what affects response to antidepressants is desperately needed.At least three biological mechanisms have been proposed to be important for causing major depression. Firstly, depressed patients tend to have shorter telomeres in their blood cells than non-depressed subjects. Telomeres are stretches of DNA at the end of each chromosome that shorten in length with our normal aging. It has been hypothesized that depressed patients have some cells which demonstrate advanced 'cellular aging' and die more readily. This could have subsequent impacts on the viability of neuronal cells and brain function.Secondly, depressed patients have higher levels of a protein called interleukin-6 in their blood. Interleukin-6 is classically involved in inflammation, but recent research suggests it interferes with brain communication and function. Thirdly, depression has been linked with abnormal function in the hippocampus, a structure in the brain which is important in regulating memory and mood. Throughout our lifetime stem cells in the hippocampus grow and generate new neurons in a continuous manner. However, it has been suggested that there is a reduction in the generation of these new neurons in depressed cases, based on evidence from animal models. Complementing this theory, antidepressants stimulate the generation of new neurons in the hippocampus. However, it remains unknown whether this is the true mechanism behind antidepressant action.Using new statistical techniques on large clinical genetic datasets we aim to test whether each of our three biological mechanisms are really causal to major depression, or whether they instead, represent an effect of having the disease. Broadly, we will achieve this using a three-step plan. Firstly, we will investigate which genes are involved in each mechanism (e.g. which genes affect telomere length). Secondly, we will combine the most significant genes affecting each mechanism into a single genetic signature. Thirdly, we will test whether genetic signatures for each mechanism predict an increased risk of major depression. A genetic signature associated with a mechanism, which additionally predicts major depression, would support the notion that this mechanism is causal. We will also test whether the genetic signature that favours generation of new neurons in the hippocampus additionally predicts patient response to antidepressants. Such an association would provide pivotal evidence towards understanding antidepressant mode of action. The two main benefits from this research include: (i) improving our understanding of which mechanisms are truly causal to major depression, which would allow for more focused research in the future and the development of preventative strategies; (ii) improving our understanding of what factors moderate antidepressant response, which may allow for the stratification of patient treatment, and the development of "add on" drugs for those genetically predisposed to respond poorly to antidepressants. Improvements in each of these two areas could save the lives of depressed patients who are at risk of suicide by providing interventions or effective treatment faster, Moreover, it could save the UK millions of pounds wasted on ineffective treatments and loss of working hours.

重度抑郁症是一种脑部疾病，影响着全球3.5亿人。抑郁症患者会经历情绪低落、失去快乐、食欲不振和睡眠困难的极端时期。目前，抗抑郁药是治疗抑郁症的一线药物，但只有三分之一的患者对第一次服用抗抑郁药有反应，三分之一的患者对多种形式的治疗没有反应。因此，迫切需要更好地了解导致重度抑郁症的原因以及影响抗抑郁药反应的因素。至少有三种生物机制被认为是导致重度抑郁症的重要因素。首先，抑郁症患者的血细胞端粒往往比非抑郁症患者短。端粒是每条染色体末端的DNA片段，随着我们正常的衰老，它的长度会缩短。据推测，抑郁症患者的一些细胞表现出“细胞老化”，更容易死亡。这可能会对神经元细胞的活力和大脑功能产生后续影响。其次，抑郁症患者血液中白细胞介素-6的含量更高。白细胞介素-6通常与炎症有关，但最近的研究表明，它会干扰大脑的交流和功能。第三，抑郁症与海马体功能异常有关，海马体是大脑中调节记忆和情绪的重要结构。在我们的一生中，海马体中的干细胞不断生长并产生新的神经元。然而，基于动物模型的证据表明，在抑郁症患者中，这些新神经元的产生有所减少。与这一理论相辅相成的是，抗抑郁药刺激海马体中新神经元的生成。然而，这是否是抗抑郁作用背后的真正机制尚不清楚。在大型临床遗传数据集上使用新的统计技术，我们的目标是测试我们的三种生物机制是否真的是导致重度抑郁症的原因，或者它们是否代表了患有这种疾病的影响。总的来说，我们将通过一个三步走的计划来实现这一目标。首先，我们将研究哪些基因参与每种机制（例如哪些基因影响端粒长度）。其次，我们将把影响每种机制的最重要的基因组合成一个单一的遗传特征。第三，我们将测试每种机制的基因特征是否能预测重度抑郁症的风险增加。与一种机制相关的基因特征，可以预测重度抑郁症，将支持这种机制是因果关系的观点。我们还将测试海马体中新神经元生成的基因特征是否能预测患者对抗抑郁药的反应。这种关联将为理解抗抑郁药的作用模式提供关键证据。这项研究的两个主要好处包括：(i)提高我们对哪些机制是真正导致重度抑郁症的原因的理解，这将允许在未来进行更有针对性的研究和制定预防策略；（ii）提高我们对抑制抗抑郁反应的因素的理解，这可能会使患者治疗分层，并为那些基因上倾向于对抗抑郁药物反应较差的人开发“附加”药物。这两个方面的改进可以通过更快地提供干预或有效的治疗来挽救处于自杀风险的抑郁症患者的生命。此外，它可以为英国节省数百万英镑浪费在无效治疗和工作时间的损失上。

项目成果

The impact of telomere shortening on human hippocampal neurogenesis: Implications for cognitive function and psychiatric disorder risk

• DOI: 10.1101/2020.04.19.049411
• 发表时间: 2020-04
• 期刊: bioRxiv
• 作者: A. Palmos;R. Duarte;Demelza M. Smeeth;Erin C. Hedges;D. Nixon;S. Thuret;T. Powell

The Psychiatric Risk Gene NT5C2 Regulates Adenosine Monophosphate-Activated Protein Kinase Signaling and Protein Translation in Human Neural Progenitor Cells

• DOI: 10.1016/j.biopsych.2019.03.977
• 发表时间: 2019-07-15
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Duarte, Rodrigo R. R.;Bechtel, Nathaniel D.;Srivastava, Deepak P.
• 通讯作者: Srivastava, Deepak P.

Telomere length and human hippocampal neurogenesis.

• DOI: 10.1038/s41386-020-00863-w
• 发表时间: 2020-12
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Palmos AB;Duarte RRR;Smeeth DM;Hedges EC;Nixon DF;Thuret S;Powell TR
• 通讯作者: Powell TR

Serum from Older Adults Increases Apoptosis and Molecular Aging Markers in Human Hippocampal Progenitor Cells.

• DOI: 10.14336/ad.2021.0409
• 发表时间: 2021-12
• 期刊: Aging and disease
• 影响因子: 7.4
• 作者: de Lucia C;Murphy T;Maruszak A;Wright P;Powell TR;Hartopp N;de Jong S;O'Sullivan MJ;Breen G;Price J;Lovestone S;Thuret S
• 通讯作者: Thuret S

Genetic predisposition to advanced biological ageing increases risk for childhood-onset recurrent major depressive disorder in a large UK sample.

• DOI: 10.1016/j.jad.2017.01.017
• 发表时间: 2017-04-15
• 期刊: Journal of affective disorders
• 影响因子: 6.6
• 作者: Michalek JE;Kepa A;Vincent J;Frissa S;Goodwin L;Hotopf M;Hatch SL;Breen G;Powell TR
• 通讯作者: Powell TR