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

我们的行为是由分子和神经递质调控的，它们在我们的大脑中扮演信使的角色。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。这使得个体接触到的一些刺激，例如药物和酒精，通过在特定时间内改变这些神经递质的水平来影响行为。打个比方，这些神经递质就像照明电路的电线一样。这些电路不仅可以通过开关控制，还可以通过调节光线水平的调光开关来控制，从而设定房间的气氛。同样，神经递质水平的改变也会改变大脑的“情绪”。如果我们把调暗器调高，房间就会非常明亮，这有助于刺激房间里的活动，如果调暗器调低，就会更放松。同样地，神经递质可能不仅仅由开/关开关控制，还由相当于调光开关的开关控制，调光开关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，DNA的某些区域可能充当这些调光开关，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，这些调节因子的DNA结构在我们所有人身上并不相同；因此，不同的个体可能将调光开关设置为不同的水平。如果这些调节调光开关在人体内出现故障，那么就很难控制正确“情绪”所需的分子数量，例如，房间里的光线水平不适合阅读等活动，或者灯可能一直亮着，或者根本就没有亮着。在一些人中，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DNA结构不同，在这些情况下，这些人可能患有行为障碍。人群中的这种遗传差异被称为多态性，可能导致对行为障碍的遗传易感性。我们的建议是找出更多关于这些调节域是如何工作的，这样就可以弄清楚如何在它们不能正常工作时修复它们，或者如何重置它们以达到正确的情绪。这些DNA调控区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以结合而调暗开关效应是由结合的蛋白质的数量和种类控制的。我们想把整个“开关”拆开，以确定所有的功能成分，然后把它重新组装起来，以找出每个位或蛋白质的作用；例如，哪一个负责调节“调光开关”的上下。要做到这一点，唯一成功的方法是试着找出通电时什么在起作用。我们把把这个装置拆开的过程称为体外方法，并找出它是如何运作的，称为体内实验，因为当我们这样做的时候，这个系统是工作的，完好无损的。我们将在提案中使用这两种方法。我们将研究的调节区域调节了血清素转运蛋白（5HTT）产生的数量。5HTT蛋白是血清素特异性再摄取抑制剂（SSRIs）的靶标，这是一种流行的抗抑郁药，因此可以预期，调节这种蛋白质在大脑中的数量或分布将对行为产生影响。越来越多的人意识到环境因素在精神疾病和其他神经疾病的进展中。这些遗传结构域导致神经递质浓度变化的机制表明，在疾病的进展中，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.