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

我们的行为受到大脑中充当信使的分子和神经递质的调节。这些神经递质产生的时间、地点和数量由来自不同来源的输入控制。这允许个人接触的一些刺激的输入，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。这些电路不仅可以由关/开开关控制，还可以由调光器开关控制，调光器开关可以改变光线水平，用于设置房间的情绪。同样，改变神经递质水平也会改变大脑的“情绪”。如果我们把调光器调高，房间会很明亮，这有助于刺激房间里的活动，如果调低调光器，会更放松。同样，神经递质可能不仅由开/关开关控制，还相当于调节大脑中这些蛋白质的数量或浓度的调光开关，从而决定我们的情绪。我们已经发现，DNA区域可能充当这些较暗的开关，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，不同的人有可能设置不同的调光开关。如果这些调节调光器的开关在人身上出现故障，那么就很难控制应该产生多少分子来调节正确的“情绪”，例如，房间里用于阅读等活动的光线水平错误，或者实际上，灯可能一直处于亮着状态，或者根本没有打开。对于一些人来说，这些控制区可能无法正常工作，因为他们的DNA结构不同于被认为是正常的，在这些情况下，这些人可能会有行为障碍。种群中的这种遗传差异被称为多态，可能导致行为障碍的遗传易感性。我们的建议是更多地了解这些监管领域是如何工作的，这样就可以找出当它们不正常工作时如何修复它们，或者如何重新设置它们以恢复正确的情绪。这些DNA调节域依次由与它们结合的蛋白质控制，有许多不同的蛋白质可能结合，而暗分子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，以确定所有的功能成分，然后再把它放在一起，找出每个比特或蛋白质的功能；例如，哪些负责调节“调光开关”的上下。要做到这一点，唯一成功的方法是尝试找出在通电时什么是正常工作的。我们把拆解这个单元的过程称为体外方法，并找出它是如何工作的活体实验，因为当我们这样做的时候，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。我们将研究的调控区域调控着一种名为5-羟色胺转运体(5HTT)的蛋白质的产生。5HTT蛋白是5-羟色胺特异性再摄取抑制剂(SSRI)的靶标，SSRI是一种流行的抗抑郁药物，因此可以预期，该蛋白在大脑中的数量或分布的调节将对行为产生影响。人们越来越多地意识到环境因素在精神和其他神经疾病的发展中的作用。这些遗传域导致神经递质浓度变化的机制表明，在疾病的发展过程中，环境可以直接与遗传易感性相互作用。

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.