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
• 负责人: Simon Luckman
• 金额: $ 59.55万
• 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: 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=BB%2FS008098%2F1
• 关键词: IPA; Anorectic; signaling; central; GDF15

Loss of appetite and the associated reduction in body weight are a major problem for old and sick people. Together they lead to a reduction in quality of life and can even cause premature death. Furthermore, treating the elderly and sick is putting an ever increasing burden on the NHS. Thus, it would be extremely useful to be able to prevent undesirable weight loss whilst protecting normal, healthy appetite.Diseased and damaged tissues release a number of chemical messengers into the bloodstream, some of which are thought to cause the feeling of sickness. One of these is a chemical called GDF15, which normally circulates at very low levels, but which is greatly increased during illnesses, including cancers and inflammatory diseases. Very recently, the site at which GDF15 works was identified - just in a very small region of the brain which has previously been associated with mediating nausea and the wish to vomit. We have identified the type of brain cell which recognises GDF15 and which mediates its effects. Thus, if we block these brain cells from sending messages in laboratory mice, we can stop GDF15 from causing eating to be reduced. Importantly, this specific brain cell type responds to GDF15, but not to other important signals which control normal appetite.In this project, we will use different types of laboratory mouse to determine where in the brain the GDF15 signal is transmitted. This will then allow us to block the signal at different sites so that, hopefully, we can reverse the appetite loss associated with a number of different illnesses, but without disrupting healthy eating. All of our experiments will be carried out in laboratory mice, but they will guide the development of drugs for use in humans. In this way, we hope to help improve outcomes for those suffering from different illnesses and, in particular, improve the quality of life for the elderly.

对于老年人和病人来说，食欲不振和体重的相关减轻是一个主要问题。它们共同导致生活质量的降低，甚至可能导致过早死亡。此外，治疗老年人和病人正在给NHS带来越来越多的负担。因此，能够防止不良的体重减轻，同时保护正常，健康的食欲，这将是非常有用的。疾病和受损的组织将许多化学信使释放到血液中，其中有些被认为会引起疾病的感觉。其中一种是一种称为GDF15的化学物质，通常以非常低的水平循环，但在疾病期间，包括癌症和炎症性疾病在内。最近，确定了GDF15作品的地点 - 仅在大脑的一个很小的区域，该区域以前与介导的恶心和呕吐的愿望有关。我们已经确定了识别GDF15并介导其作用的脑细胞的类型。因此，如果我们阻止这些脑细胞在实验室小鼠中发送消息，我们可以阻止GDF15减少饮食。重要的是，这种特定的脑细胞类型对GDF15做出了反应，但对控制正常食欲的其他重要信号不反应。在该项目中，我们将使用不同类型的实验室小鼠来确定在大脑中gdf15信号在何处传播。然后，这将使我们能够在不同的地点阻止信号，以便我们可以扭转与许多不同疾病相关的食欲损失，但不会破坏健康的饮食。我们所有的实验都将在实验室小鼠中进行，但它们将指导用于人类使用的药物的开发。通过这种方式，我们希望帮助改善患有不同疾病的人的结果，尤其是改善老年人的生活质量。

项目成果

Brainstem peptides and peptidergic neurons in the regulation of appetite

• DOI: 10.1016/j.coemr.2022.100339
• 发表时间: 2022-03
• 期刊: Current Opinion in Endocrine and Metabolic Research
• 作者: Giuseppe D’Agostino;S. Luckman

Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation.

• DOI: 10.1016/j.molmet.2021.101407
• 发表时间: 2022-01
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Costa A;Ai M;Nunn N;Culotta I;Hunter J;Boudjadja MB;Valencia-Torres L;Aviello G;Hodson DJ;Snider BM;Coskun T;Emmerson PJ;Luckman SM;D'Agostino G
• 通讯作者: D'Agostino G