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.

英国近三分之二的人口现在超重或肥胖。这导致多种相关疾病，包括高血压，这可能会增加遭受心脏病或中风的机会。肥胖及其相关疾病的成本也对NHS造成了极大的压力。体重和血压之间存在直接关系。因此，体重越高，您的体重越大，高血压就越多。但是，目前，尚不清楚导致这种直接关系的主要因素是什么。一个建议是，肥胖者产生了许多激素，称为瘦素，通常在大脑上作用以尝试减轻体重的增加。但是，这样做，瘦素也可能间接导致血压升高。我们希望了解脑瘦素中可以产生这种作用的位置，就像我们以前所做的那样表明瘦素在哪里影响体重。例如，瘦素可以通过激活神经细胞（神经元）来增加我们燃烧的卡路里数量，而神经细胞（神经元）位于大脑的微小区域，称为下丘脑（或DMH）的背侧核。这些神经元包含一个名为PRRP的使者。我们现在有人类有证据表明PRRP及其受体之间以及肥胖之间的联系。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，我们已经表明，其PRRP受体中有突变的小鼠的血压也低。因此，DMH中的PRRP神经元能否对肥胖患者的瘦素反应并负责其高血压？首先，我们将产生与人类相同突变的小鼠，以便我们可以研究该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电路，以确定瘦素和PRRP的影响。我们能够研究大脑中神经元的极其复杂的网络，因为我们可以在小鼠中看到不同类型的PRRP神经元，因为它们已被荧光发光。我们可以记录这些神经元的活性，同时刺激与它们相连的其他细胞 - 全部在培养皿中！但是，也非常新的是，我们可以刺激小鼠的特定类型的神经元，而它们的表现正常。这可以通过给小鼠注射“设计师药物”，或使用光纤向小鼠的大脑闪烁。我们还可以抑制同一神经元的活性，并了解小鼠对我们的反应，从而实验降低血压。通过这样做，我们可以看到与正常小鼠相比，不起作用PRRP神经元的小鼠是否会难以抵消低血压。这将使我们能够研究PRRP在血压健康控制中的作用，以及小鼠和人类突变的后果。重要的是，这将有助于我们确定肥胖是如何与高血压联系起来的，这可能会导致肥胖患者量身定制的疗法。

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