Genetic interrogation of central circuit regulating blood pressure

调节血压的中枢回路的基因询问

• 批准号: BB/P01867X/1
• 负责人: Simon Luckman
• 金额: $ 60.98万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP01867X%2F1
• 关键词: Genetic; interrogation; central; circuit; regulating

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.

近三分之二的英国人现在超重或肥胖。这会导致许多相关疾病，包括高血压，这会增加患心脏病或中风的机会。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，体重越高，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，肥胖的人会分泌大量一种叫做瘦素的激素，这种激素通常作用于大脑，试图抑制体重的增加。然而，在这样做的过程中，瘦素也可能间接导致血压升高。我们希望了解大脑中瘦素在哪里产生这种影响，正如我们之前所做的那样，瘦素在哪里影响体重。例如，瘦素可以通过激活大脑中一个叫做下丘脑背内侧核（DMH）的小区域的神经细胞（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表明PrRP及其受体与肥胖之间存在联系。许多肥胖患者已被确定为编码PrRP受体的基因发生突变。有趣的是，这些患者的血压低于预期。此外，我们已经证明，PrRP受体发生突变的老鼠也有低血压。那么，肥胖患者的DMH中的PrRP神经元是否会对瘦素做出反应，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，这样我们就可以研究这种基因在实验动物中的功能。然后我们可以研究大脑中的复杂回路，以确定瘦素和PrRP是如何起作用的。我们能够研究大脑中极其复杂的神经元网络，因为我们可以在老鼠身上看到不同类型的神经元，比如PrRP神经元，因为它们在荧光灯下发光。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完成！然而，同样新颖的是，我们可以在老鼠行为完全正常的时候刺激它们体内特定类型的神经元。这可以通过给老鼠注射一种“设计药物”来实现，也可以通过使用光纤将光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，观察老鼠对我们的反应，通过实验降低它们的血压。通过这样做，我们可以看到，与正常小鼠相比，没有PrRP神经元功能的小鼠是否更难以抵抗低血压。这将使我们能够研究PrRP在健康控制血压中的作用，以及在小鼠和人类中突变的后果。重要的是，它将帮助我们确定肥胖与高血压之间的联系，这可能会为肥胖患者提供量身定制的治疗方法。

项目成果

A rare human variant that disrupts GPR10 signalling causes weight gain in mice.

• DOI: 10.1038/s41467-023-36966-3
• 发表时间: 2023-03-15
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Talbot, Fleur;Feetham, Claire H.;Mokrosinski, Jacek;Lawler, Katherine;Keogh, Julia M.;Henning, Elana;de Oliveira, Edson Mendes;Ayinampudi, Vikram;Saeed, Sadia;Bonnefond, Amelie;Arslan, Mohammed;Yeo, Giles S. H.;Froguel, Philippe;Bechtold, David A.;Adamson, Antony;Humphreys, Neil;Barroso, Ines;Luckman, Simon M.;Farooqi, I. Sadaf
• 通讯作者: Farooqi, I. Sadaf