IPA: Anorectic signaling by the central GDF15/GFRAL system

食欲不振和由此引起的体重下降是老年人和病人面临的一个主要问题。它们共同导致生活质量下降，甚至可能导致过早死亡。此外，治疗老人和病人给NHS带来了越来越大的负担。因此，它将是非常有用的，能够防止不必要的体重下降，同时保护正常，健康的食欲。患病和受损的组织会向血液中释放大量的化学信使，其中一些被认为会引起恶心的感觉。其中之一是一种叫做GDF15的化学物质，它通常在很低的水平循环，但在疾病期间，包括癌症和炎症性疾病，它会大大增加。最近，GDF15起作用的位置被确定了——就在大脑的一个非常小的区域，这个区域以前被认为与恶心和呕吐的愿望有关。我们已经确定了识别GDF15并调节其作用的脑细胞类型。因此，如果我们阻止这些脑细胞在实验室老鼠身上传递信息，我们就可以阻止GDF15导致进食减少。重要的是，这种特殊的脑细胞类型对GDF15有反应，但对控制正常食欲的其他重要信号没有反应。在这个项目中，我们将使用不同类型的实验室小鼠来确定GDF15信号在大脑中的传输位置。这将使我们能够在不同的部位阻断信号，这样，我们就有希望扭转与许多不同疾病相关的食欲下降，但不会破坏健康的饮食。我们所有的实验都将在实验室老鼠身上进行，但它们将指导用于人类的药物的开发。通过这种方式，我们希望帮助改善那些患有不同疾病的人的结果，特别是提高老年人的生活质量。

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.