Genetic interrogation of central circuit regulating blood pressure

英国近三分之二的人口超重或肥胖。这会导致许多相关疾病，包括高血压，这会增加心脏病发作或中风的几率。肥胖及其相关疾病的费用也给NHS带来了极大的压力。体重和血压之间有直接的关系。因此，你的体重越高，你患高血压的可能性就越大。然而，目前还不清楚导致这种直接关系的主要因素是什么。一种说法是肥胖的人会产生大量的一种叫做瘦素的激素，这种激素通常作用于大脑，试图减缓体重的增加。然而，在这样做的时候，瘦素也可能间接导致血压升高。我们希望了解瘦素在大脑中的哪个部位可以产生这种效应，就像我们之前所做的那样，以显示瘦素在哪里影响体重。例如，瘦素可以通过激活位于大脑一个叫做下丘脑背内侧核（或DMH）的微小区域的神经细胞（神经元）来增加我们燃烧的卡路里数量。这些神经元含有一种叫做PrRP的信使，我们现在有来自人类的证据证明PrRP和它的受体之间的联系，以及与肥胖的联系。已经鉴定出许多肥胖患者在编码PrRP受体的基因中具有突变。有趣的是，这些患者的血压低于预期。此外，我们已经证明，在PrRP受体中具有突变的小鼠也具有低血压。那么，DMH中的PrRP神经元是否会对肥胖患者的瘦素产生反应，并对他们的高血压负责？首先，我们将产生具有与人类相同突变的小鼠，以便我们可以在实验动物中研究该基因的功能。然后，我们可以研究大脑中复杂的回路，以确定瘦素和PrRP如何发挥作用。我们能够研究大脑中极其复杂的神经元网络，因为我们可以看到不同类型的神经元，例如小鼠中的PrRP神经元，因为它们已经被荧光灯照射。我们可以记录这些神经元的活动，同时刺激与它们相连的其他细胞-所有这些都在培养皿中！然而，同样非常新颖的是，我们可以刺激小鼠中特定类型的神经元，而它们的行为完全正常。这可以通过给老鼠注射一种“特制药物”或用光纤将光线照射到老鼠的大脑中来实现。我们还可以抑制相同神经元的活动，看看老鼠对我们实验性降低血压的反应。通过这样做，我们可以看到与正常小鼠相比，没有功能性PrRP神经元的小鼠是否更难对抗低血压。这将使我们能够研究PrRP在健康控制血压中的作用，以及小鼠和人类突变的后果。重要的是，它将帮助我们确定肥胖与高血压的关系，这可能会为肥胖患者提供量身定制的治疗方法。

Nearly two-thirds of the UK population is now overweight or obese. This leads to a multitude of related diseases, including high blood pressure, which can increase the chances of suffering a heart attack or stroke. The costs of obesity and its related diseases also put extreme pressure on the NHS.There is a direct relationship between body weight and blood pressure. Thus, the higher your weight the more likely you will suffer from high blood pressure. However, currently, it is unknown what the major factors are which lead to this direct relationship. One suggestion is that obese people produce a lot of a hormone, called leptin, which normally acts on the brain to try and moderate increasing weight. However, in doing this, leptin may also indirectly cause increased blood pressure. We wish to understand where in the brain leptin can have this effect, as we have done previously to show where leptin acts to affect body weight. For example, leptin can increase the number of calories we burn by activating nerve cells (neurones) which lie in a tiny region of the brain called the dorsomedial nucleus of the hypothalamus (or DMH). These neurones contain a messenger called PrRP.We now have evidence from humans for links between PrRP and its receptor, and with obesity. A number of obese patients have been identified who have mutations in the gene that encodes for the PrRP receptor. Interestingly, these patients have lower than expected blood pressure. Furthermore, we have shown that mice that have mutations in their PrRP receptor also have low blood pressure. So, could PrRP neurones in the DMH respond to leptin in obese patients and be responsible for their high blood pressure? To start with we will generate mice that have the same mutations as found in humans, so that we can study the functioning of this gene in an experimental animal. Then we can study the complex circuits in the brain to determine how leptin and PrRP have their effects. We are able to study the extremely complex network of neurones in the brain because we can see the different types, such as the PrRP neurones, in mice because they have been made to shine with fluorescent light. We can record the activity of these neurones while stimulating the other cells that connect with them - all in a petri dish! However, what is also very new is that we can stimulate specific types of neurone in mice while they are behaving perfectly normally. This can be done by either giving the mice an injection of a "designer drug" or by shining light into the mouse's brain using an optic fibre. We can also inhibit the activity of the same neurones and see how the mice respond to us experimentally lowering their blood pressure. By doing this, we can see whether mice without functioning PrRP neurones find it more difficult to counteract low blood pressure when compared with normal mice. This will allow us to study the role of PrRP in the healthy control of blood pressure, as well as the consequences of mutations in both mice and humans. Importantly, it will help us determine how obesity is linked with high blood pressure, which potentially could lead to tailored therapies for obese patients.