The mechanisms by which polymorphic domains in the 5HTT gene potentially correlated with behavioural disorders modulate gene expression

5HTT 基因中与行为障碍潜在相关的多态性结构域调节基因表达的机制

• 批准号: BB/D016754/1
• 负责人: John Quinn
• 金额: $ 50.1万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FD016754%2F1
• 关键词: mechanisms; polymorphic; domains; 5HTT; gene

Our behaviour is modulated by molecules, neurotransmitters, in our brain that act as messengers. When, where and how much of these neurotransmitters are produced is controlled by inputs from various sources. This allows input from a number of stimuli that an individual is exposed to, e.g. drugs and alcohol, to affect behaviour by changing the levels of these neurotransmitters for a specific length of time. An analogy would be that these neurotransmitters act like the electrical wiring of a lighting circuit. These circuits can not only be controlled by an off/on switch, but also by dimmer switches which alter the level of light and are used to set the mood in a room. Similarly altering levels of neurotransmitters would alter the 'mood' of the brain. If we set the dimmer high, the room is very bright and this helps to stimulate activity in the room, if the dimmer is set low, it is more relaxing. In the same way neurotransmitters may not be controlled solely by on/off switches but also by the equivalent of dimmer switches that modulate the amount or concentration of these proteins in the brain so setting our mood. We have found regions of DNA that might act as these dimmer switches to control how much of a neurotransmitter is produced in specific areas of the brain. Importantly these regions can respond to the physiological and psychological stresses as well as drugs that alter our behaviour. The interesting thing is that the DNA structure of these regulators is not the same in all of us; hence different individuals have dimmer switches potentially set to different levels. If these regulatory dimmer switches malfunction in people then it's very hard to control the amount of molecule that should be made for the correct 'mood', e.g. the wrong level of light in the room for activities such as reading or indeed the light might be on all the time or not switched on at all. In some people these control regions might not work correctly because their DNA structure is different from what would be considered 'normal' and in these cases these people may have behavioural disorders. Such genetic differences in the population are called polymorphisms and can result in a genetic predisposition to a behavioural disorder. We propose is to find out more about how these regulatory domains work so that can figure out how to fix them when they don't work properly or how to reset them for the correct mood. These DNA regulatory domains are controlled in turn by proteins that bind to them, there are many different proteins that may bind and the dimmer switch effect is controlled by how many and what kind of protein is binding. We want to take the whole 'switch' apart to identify all the functional components and then put it back together to find out what each bit or protein does; e.g. which ones are responsible for turning the 'dimmer switch' up and down. The only successful way to do this is to try and find out what is functional when the electricity is turned on. We call the process of taking the unit apart an in vitro approach and finding out how it functions an in vivo experiment, because the system is working and intact when we do it. We will use both approaches in our proposal. The regulatory domains we will study regulate how much of a protein called the serotonin transporter (5HTT) is produced. The 5HTT protein is a target for serotonin specific reuptake inhibitors (SSRIs) a popular class of antidepressants, therefore it would be expected that modulation of the amount or distribution of this protein in the brain would have affects on behaviour. There is a growing awareness of environmental factors in the progression of psychiatric and other neurological disorders. The mechanism by which these genetic domains bring about changes in concentrations of neurotransmitters demonstrates a mechanism by which environment can directly interact with genetic predisposition in the progression of a disorder.

我们的行为是由分子，神经递质，在我们的大脑中作为信使调节的。这些神经递质产生的时间、地点和数量由各种来源的输入控制。这允许来自个体暴露于的许多刺激的输入，例如药物和酒精，通过在特定时间长度内改变这些神经递质的水平来影响行为。一个类比是，这些神经递质的作用就像照明电路的电线。这些电路不仅可以通过关/开开关控制，还可以通过调光开关来改变光线水平，并用于设置房间的气氛。同样，改变神经递质的水平也会改变大脑的“情绪”。如果我们将调光器设置为高，房间非常明亮，这有助于刺激房间中的活动，如果调光器设置为低，则更放松。同样，神经递质可能不仅仅是由开关控制的，也是由相当于调光开关的东西控制的，它调节大脑中这些蛋白质的数量或浓度，从而设定我们的情绪。我们已经发现了可能充当这些调光开关的DNA区域，以控制大脑特定区域产生多少神经递质。重要的是，这些区域可以对生理和心理压力以及改变我们行为的药物做出反应。有趣的是，这些调节器的DNA结构在我们所有人中并不相同;因此，不同的个体有可能将调光开关设置到不同的水平。如果这些调节调光器开关在人身上发生故障，那么就很难控制应该为正确的“情绪”制造的分子量，例如，房间中用于阅读等活动的光线水平错误，或者实际上灯可能一直亮着或根本不亮。在某些人中，这些控制区域可能无法正常工作，因为他们的DNA结构与被认为是“正常”的不同，在这些情况下，这些人可能有行为障碍。群体中的这种遗传差异被称为多态性，并可能导致行为障碍的遗传倾向。我们建议更多地了解这些监管领域是如何工作的，以便找出如何在它们不正常工作时修复它们，或者如何将它们重置为正确的情绪。这些DNA调控结构域依次由与其结合的蛋白质控制，有许多不同的蛋白质可以结合，并且调光开关效应由结合的蛋白质的数量和种类控制。我们想把整个“开关”拆开，以识别所有的功能组件，然后把它放回一起，以找出每个比特或蛋白质的作用;例如，哪些比特或蛋白质负责把“调光开关”调高或调低。要做到这一点，唯一成功的方法是尝试找出通电时的功能。我们称将单元拆开的过程为体外方法，并找出其功能的过程为体内实验，因为当我们这样做时，系统正在工作并且完好无损。我们将在我们的提案中使用这两种方法。我们将研究的调节域调节了一种名为5-羟色胺转运蛋白（5 HTT）的蛋白质的产生量。5 HTT蛋白是5-羟色胺特异性再摄取抑制剂（SSRIs）的靶点，SSRIs是一种流行的抗抑郁药，因此可以预期，这种蛋白在大脑中的量或分布的调节将对行为产生影响。越来越多的人意识到环境因素在精神疾病和其他神经系统疾病的进展中的作用。这些遗传结构域引起神经递质浓度变化的机制证明了环境可以直接与疾病进展中的遗传易感性相互作用的机制。

项目成果

Combinatorial interaction between two human serotonin transporter gene variable number tandem repeats and their regulation by CTCF.

• DOI: 10.1111/j.1471-4159.2009.06453.x
• 发表时间: 2010-01
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Ali FR;Vasiliou SA;Haddley K;Paredes UM;Roberts JC;Miyajima F;Klenova E;Bubb VJ;Quinn JP
• 通讯作者: Quinn JP

Behavioural genetics of the serotonin transporter.

• DOI: 10.1007/7854_2011_186
• 发表时间: 2012
• 期刊: Current topics in behavioral neurosciences
• 作者: K. Haddley;V. Bubb;G. Breen;U. M. Parades-Esquivel;J. Quinn

Intronic tandem repeat in the serotonin transporter gene in Old World monkeys: a new transcriptional regulator?

旧世界猴子血清素转运蛋白基因的内含子串联重复：一种新的转录调节因子？

• DOI: 10.1007/s12031-011-9664-6
• 发表时间: 2012
• 期刊: MN
• 作者: Paredes UM

Generation of a transgenic model to address regulation and function of the human neurokinin 1 receptor (NK1R).

生成转基因模型来解决人类神经激肽 1 受体 (NK1R) 的调节和功能。

• DOI: 10.1016/j.npep.2007.04.005
• 发表时间: 2007
• 期刊: Neuropeptides
• 影响因子: 2.9
• 作者: Vasiliou AS

Assessing the impact of genetic variation on transcriptional regulation in vitro.

评估遗传变异对体外转录调控的影响。

• DOI: 10.1007/978-1-60327-367-1_11
• 发表时间: 2010
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Ali FR