Molecular characterization in human neurons of genes associated with severe obesity identified from consanguineous pedigrees.

从近亲谱系中鉴定出的与严重肥胖相关的人类神经元基因的分子特征。

• 批准号: MR/S026193/1
• 负责人: Giles Yeo
• 金额: $ 129.2万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS026193%2F1
• 关键词: Molecular; characterization; human; neurons; genes

Obesity is a growing public health problem. While it has undoubtedly been driven by the changing environment, there is a large heritable component underlying the variation in body-weight within the population. Genetic studies point to the brain, in particular a region called the hypothalamus, as having a crucial role in modulating appetite. For example, mutations of single genes in the hypothalamic leptin melanocortin pathway leads to severe, early-onset obesity. Around 10% of severe human obesity currently has a clear identified cause, with the majority of mutations sitting within the genes encoding the melanocortin pathway. Thus, much of the genetic aetiology of severe obesity remains to be uncovered, identification of which could reveal novel pathways and potential therapeutic targets. However, studying the disease in inbred populations increases the chances of finding disease causing mutations. Using this approach, we have identified mutations in two new genes, ADCY3 and ROCK1, that are associated with severe obesity. In this proposal, we will study both these genes in detail. Given the role of the brain in the regulation of body-weight and food intake, we will characterize these genes in human neurons. We need to understand not only the function of these genes in normal cells but also the consequences of loss of function for the neuronal populations in which they are expressed. Although murine models have been hugely helpful in the past to overcome the difficulties of inaccessibility of the human hypothalamus, we believe studying human tissue from the relevant regions is essential to get a fuller understanding of the role of these genes. An existing collaboration with the Cambridge Brain Bank, allows us access to fresh and fixed human donor brain samples. The access to this precious material, coupled with recent developments in single cell sequencing and mapping technologies provides us with a timely opportunity to study where these genes are expressed in the human hypothalamus. Additionally, we have recently acquired the ability to generate, genetically manipulate and differentiate human stem-cells into hypothalamic neurons. This will allow us to directly examine the impact of these obesity associated mutations in the context of a relevant human cell. Using high-throughput DNA sequencing approaches, we will also continue our search for other new obesity candidates. Our current proposal is a collaborative venture between two UK centres of excellence in the study of the genetics of obesity. The group of Froguel, from Imperial College London, brings a large collection of severely obese children from highly consanguineous Pakistani pedigrees; and the group of Coll, O'Rahilly and Yeo, from the MRC Metabolic Diseases Unit at the University of Cambridge, who bring bespoke functional expertise and access to human hypothalamic samples. Our aim is to uncover novel appetite control pathways and reveal new potential therapeutic targets in order to tackle obesity.

肥胖是日益增长的公共卫生问题。尽管它无疑是由不断变化的环境驱动的，但人口内部体重变化的基础很大。遗传研究指出了大脑，特别是一个称为下丘脑的区域，在调节食欲中具有至关重要的作用。例如，下丘脑瘦素黑色皮质素途径中单基因的突变导致严重的早期发作的肥胖。目前约有10％的严重人肥胖症有明确的原因，大多数突变位于编码黑色素性素途径的基因内。因此，严重肥胖症的许多遗传病因仍然待发现，其鉴定可以揭示新的途径和潜在的治疗靶标。但是，研究近​​交疾病的疾病增加了发现引起突变的疾病的机会。使用这种方法，我们已经确定了与严重肥胖有关的两个新基因ADCY3和ROCK1中的突变。在此提案中，我们将详细研究这两个基因。鉴于大脑在体重和食物摄入调节中的作用，我们将在人类神经元中表征这些基因。我们不仅需要理解这些基因在正常细胞中的功能，而且还需要了解它们表达的神经元种群的功能丧失的后果。尽管过去的鼠模型对克服人类下丘脑的难以及性难度的困难非常有帮助，但我们认为，从相关地区研究人体组织对于获得对这些基因的作用的更全面了解至关重要。与剑桥大脑库进行的现有合作使我们可以访问新鲜和固定的人类供体脑样本。对这种珍贵材料的访问，再加上单细胞测序和映射技术的最新发展，为我们提供了及时研究这些基因在人类下丘脑中表达的地方的机会。此外，我们最近获得了产生，遗传操纵和区分人类干细胞为下丘脑神经元的能力。这将使我们能够在相关人类细胞的背景下直接检查这些相关突变的影响。使用高通量DNA测序方法，我们还将继续搜索其他新的肥胖候选者。我们目前的提议是在肥胖遗传学研究中，英国两个卓越中心之间的合作企业。来自伦敦帝国学院的弗罗格尔（Froguel）团体为巴基斯坦高度近亲的家族带来了大量肥胖的孩子。以及剑桥大学的MRC代谢疾病部门的Coll，O'Rahilly和Yeo小组，他们带来了定制的功能专业知识并获得人类下丘脑样本。我们的目的是发现新型食欲控制途径并揭示新的潜在治疗靶标，以应对肥胖症。

项目成果

Biallelic mutations in P4HTM cause syndromic obesity

P4HTM 双等位基因突变导致综合征性肥胖

• DOI: 10.2337/figshare.22577353.v1
• 发表时间: 2023
• 作者: Froguel P

A survey of the mouse hindbrain in the fed and fasted state using single-nucleus RNA sequencing

使用单核 RNA 测序对进食和禁食状态下的小鼠后脑进行调查

• DOI: 10.1101/2021.03.11.434948
• 发表时间: 2021
• 作者: Dowsett G

A program of successive gene expression in mouse one-cell embryos

• DOI: 10.1016/j.celrep.2023.112023
• 发表时间: 2023-01-31
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Asami, Maki;Lam, Brian Y. H.;Perry, Anthony C. F.
• 通讯作者: Perry, Anthony C. F.

The vagus nerve mediates the physiological but not pharmacological effects of PYY3-36 on food intake.

迷走神经介导 PYY3-36 对食物摄入的生理作用，但不介导药理作用。

• DOI: 10.1016/j.molmet.2024.101895
• 发表时间: 2024
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Alonso AM

Human embryonic genome activation initiates at the one-cell stage.

• DOI: 10.1016/j.stem.2021.11.012
• 发表时间: 2022-02-03
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Asami M;Lam BYH;Ma MK;Rainbow K;Braun S;VerMilyea MD;Yeo GSH;Perry ACF
• 通讯作者: Perry ACF