Dissecting populations of PrRP neurone in conditional transgenic mice

解剖条件转基因小鼠的 PrRP 神经元群体

基本信息

  • 批准号:
    BB/H007172/1
  • 负责人:
  • 金额:
    $ 53.44万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2010
  • 资助国家:
    英国
  • 起止时间:
    2010 至 无数据
  • 项目状态:
    已结题

项目摘要

In order to survive, we need to balance our energy intake (the food we eat) with metabolic demands. The latter includes the energy we require to keep warm, exercise and maintain body functions. We must ensure that there is adequate energy easily available in the form of glucose and stored in the form of fat, and predict any changes in demand. To do this, the brain and particularly regions of the hypothalamus and brainstem, collect information from other organs regarding whether we have recently eaten, the time of day, how much glucose is in our blood and how much fat is laid down in adipose tissue. All of this information is integrated by specific brain cells and translated into actions, again by peripheral organs: should we eat, produce more warmth, release more energy from stores? Our problem is that we know relatively little about the kinds of brain cell (neurone) which carry out this key integrative function. However, we have demonstrated that a novel brain transmitter, called PrRP, is capable of regulating many of these critical responses to changing energy demands, and that mice lacking the receptor for PrRP are obese. More interestingly, PrRP is produced in distinct populations of neurone in the exact regions of the hypothalamus and brainstem mentioned. However, the problem remains how to study or manipulate these distinct neurones in their different environments. We have a unique opportunity to bring together the very best physiological and behavioural analyses with cutting-edge genetics. Using the latest techniques we will produce transgenic mice with harmless alterations to the genes expressed in PrRP neurones. The first type of mouse will express a fluorescent marker only in PrRP neurones which will allow us to visualise them amongst the millions of cells in the brain. We will then be able to record their electrical activity and determine how they respond to different stimuli. This mouse will also allow us to selectively silence signalling molecules, thus demonstrating the importance of different signals specifically to PrRP neurones. The second mouse will have a small piece of DNA inserted into the PrRP gene to disrupt its expression. We predict that this mouse will be obese because it cannot respond to metabolic signals to produce the normal regulatory responses. However, we can cross this mouse with others which will result in the insert being removed from the PrRP gene in specific populations of PrRP neurone. This will allow us to study mice in which PrRP now functions normally in the brainstem alone and then also in the hypothalamus. Through these studies we will gain important insight into the brain circuitry controlling energy balance and that will perhaps allow us to develop new strategies to fight the burgeoning obesity epidemic.
为了生存,我们需要平衡能量摄入(我们吃的食物)和代谢需求。后者包括我们保暖、锻炼和维持身体功能所需的能量。我们必须确保有足够的能量以葡萄糖的形式轻松获得并以脂肪的形式储存,并预测需求的任何变化。为此,大脑,特别是下丘脑和脑干区域,从其他器官收集信息,包括我们最近是否进食、一天中的时间、血液中的葡萄糖含量以及脂肪组织中的脂肪含量。所有这些信息都由特定的脑细胞整合并转化为行动,再由周围器官转化为行动:我们应该吃东西,产生更多的热量,从储存中释放更多的能量吗?我们的问题是,我们对执行这一关键综合功能的脑细胞(神经元)种类知之甚少。然而,我们已经证明,一种称为 PrRP 的新型大脑递质能够调节许多对不断变化的能量需求的关键反应,并且缺乏 PrRP 受体的小鼠是肥胖的。更有趣的是,PrRP 是在所提到的下丘脑和脑干的确切区域中的不同神经元群体中产生的。然而,问题仍然是如何在不同的环境中研究或操纵这些不同的神经元。我们有一个独特的机会将最好的生理和行为分析与尖端遗传学结合起来。使用最新技术,我们将生产出对 PrRP 神经元表达的基因进行无害改变的转基因小鼠。第一种类型的小鼠仅在 PrRP 神经元中表达荧光标记,这将使我们能够在大脑中数百万个细胞中可视化它们。然后我们将能够记录他们的电活动并确定他们对不同刺激的反应。这种小鼠还允许我们选择性地沉默信号分子,从而证明不同信号对 PrRP 神经元的重要性。第二只小鼠将在 PrRP 基因中插入一小段 DNA,以破坏其表达。我们预测这只小鼠会肥胖,因为它无法对代谢信号做出反应以产生正常的调节反应。然而,我们可以将该小鼠与其他小鼠杂交,这将导致特定 PrRP 神经元群体中 PrRP 基因中的插入片段被移除。这将使我们能够研究 PrRP 现在仅在脑干以及下丘脑中正常发挥作用的小鼠。通过这些研究,我们将获得对控制能量平衡的大脑回路的重要见解,这或许将使我们能够制定新的策略来对抗迅速蔓延的肥胖流行病。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Physiological Roles of GPR10 and PrRP Signaling.
  • DOI:
    10.3389/fendo.2013.00020
  • 发表时间:
    2013-01-01
  • 期刊:
  • 影响因子:
    5.2
  • 作者:
    Dodd, Garron T;Luckman, Simon M
  • 通讯作者:
    Luckman, Simon M
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:
  • 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
The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus.
  • DOI:
    10.1016/j.cmet.2014.07.022
  • 发表时间:
    2014-10-07
  • 期刊:
  • 影响因子:
    29
  • 作者:
    Dodd GT;Worth AA;Nunn N;Korpal AK;Bechtold DA;Allison MB;Myers MG Jr;Statnick MA;Luckman SM
  • 通讯作者:
    Luckman SM
Brainstem peptides and peptidergic neurons in the regulation of appetite
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Simon Luckman其他文献

Simon Luckman的其他文献

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{{ truncateString('Simon Luckman', 18)}}的其他基金

IPA: Mechanisms that elicit weight loss with selective peptide agonism
IPA:通过选择性肽激动作用引起体重减轻的机制
  • 批准号:
    BB/W000989/1
  • 财政年份:
    2022
  • 资助金额:
    $ 53.44万
  • 项目类别:
    Research Grant
The brainstem signals dual motivational valence following ingestion
摄入后脑干发出双重动机效价信号
  • 批准号:
    MR/T032669/1
  • 财政年份:
    2020
  • 资助金额:
    $ 53.44万
  • 项目类别:
    Research Grant
IPA: Anorectic signaling by the central GDF15/GFRAL system
IPA:中央 GDF15/GFRAL 系统的厌食信号传导
  • 批准号:
    BB/S008098/1
  • 财政年份:
    2019
  • 资助金额:
    $ 53.44万
  • 项目类别:
    Research Grant
Oxytocin pathways affecting metabolism
影响新陈代谢的催产素途径
  • 批准号:
    MR/P024017/1
  • 财政年份:
    2017
  • 资助金额:
    $ 53.44万
  • 项目类别:
    Research Grant
A glucose-responsive network
葡萄糖反应网络
  • 批准号:
    MR/R002991/1
  • 财政年份:
    2017
  • 资助金额:
    $ 53.44万
  • 项目类别:
    Research Grant
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
  • 财政年份:
    2017
  • 资助金额:
    $ 53.44万
  • 项目类别:
    Research Grant
Distinct forebrain system regulating arousal
独特的前脑系统调节唤醒
  • 批准号:
    BB/R003858/1
  • 财政年份:
    2017
  • 资助金额:
    $ 53.44万
  • 项目类别:
    Research Grant
Reward networks and appetitive behaviour
奖励网络和食欲行为
  • 批准号:
    BB/N007549/1
  • 财政年份:
    2016
  • 资助金额:
    $ 53.44万
  • 项目类别:
    Research Grant
A thermogenic circuit that maintains sensitivity to leptin in obesity
维持肥胖患者对瘦素敏感性的生热回路
  • 批准号:
    BB/L021129/1
  • 财政年份:
    2014
  • 资助金额:
    $ 53.44万
  • 项目类别:
    Research Grant
Defining a gut-brain-liver axis
定义肠-脑-肝轴
  • 批准号:
    BB/M001067/1
  • 财政年份:
    2014
  • 资助金额:
    $ 53.44万
  • 项目类别:
    Research Grant

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