How food speaks to you: A new brain-gut axis for lifelong health.

食物如何与你对话：终身健康的新脑肠轴。

• 批准号: BB/X015106/1
• 负责人: Rebecca Taylor
• 金额: $ 54.81万
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX015106%2F1
• 关键词: How; food; speaks; new; brain

What we eat has a major impact on our lifelong health. Being overweight causes multiple diseases, the severity of which is exacerbated by age. This makes understanding how diet impacts the ageing process, and finding ways to manipulate it, an important priority for research and public health policy. Nutrition is a known modulator of longevity. It is possible to increase lifespan and improve age-related health by modulating food intake eg. dietary restriction or intermittent fasting, or even by simply smelling changes in nutrient levels. This project investigates what connects the sensing of nutrition by the brain with changes to other metabolic tissues like the gut (henceforth referred to as the brain-gut axis), and links this to eating behaviours, metabolic health, and ageing. Identifying new molecular targets implicated in the nutrition-brain-gut response provides tangible methods to treat age-associated pathologies and improve health. Recently the Taylor and Tullet labs independently identified and published two compelling candidate pathways that connect nutrient perception to age-related health. These are the NF-E2 related transcription factor (Nrf) and the Unfolded Protein Response (UPR) of the endoplasmic reticulum (ER). This collaborative grant brings together our past work and new preliminary data to complete the picture. We hypothesise that Nrf acts in neurons to communicate information about diet and regulate UPR activation in the gut. This sequence of events will then control nutrient regulated feeding behaviours, metabolism and age-related health.The work proposed here will use the nematode worm Caenorhabditis elegans to investigate the brain-gut relationship between these two pathways. The worm is perfect for this as it comes with a ready-made genetic toolkit, including: mutants that allow us to study the function of specific genes/molecules; fluorescent reporters allowing us to see where and when molecules are switched on or off; and a fully mapped nervous system so that we know exactly which neurons signal to each other. This useful and cost-effective model will allow us to establish the molecular sequence of events from the sensing of food, to neuronal Nrf signalling, to UPR activation. In addition, these tiny animals are excellent models for eating behaviour, age-related health, and lifespan, allowing us to probe the impact of molecular change on these processes. Identifying the molecular mechanisms that connect nutrient information with effects on metabolic health and ageing would enable the development of therapies that harness these mechanisms or target their specific molecular functions in order to therapeutically manipulate ageing and health, providing avenues to delay and treat both diet-induced and other non-communicable diseases associated with age.

我们的饮食对我们的终生健康有重大影响。超重会导致多种疾病，随着年龄的增长，这些疾病的严重性会加剧。这使得了解饮食如何影响衰老过程，并找到控制它的方法，成为研究和公共卫生政策的重要优先事项。众所周知，营养是延年益寿的调节因素。通过调节食物摄入量来延长寿命和改善与年龄相关的健康是可能的。饮食限制或间歇性禁食，甚至只是闻到营养水平的变化。这个项目研究大脑对营养的感知与肠道(此后称为大脑-肠轴)等其他代谢组织的变化之间的联系，并将其与饮食行为、新陈代谢健康和衰老联系起来。识别与营养-大脑-肠道反应有关的新分子靶点为治疗与年龄相关的疾病和改善健康提供了切实的方法。最近，泰勒实验室和图莱特实验室独立确定并发表了两条引人注目的候选路径，将营养感知与年龄相关的健康联系起来。它们是核因子-E2相关转录因子(NRF)和内质网(ER)的未折叠蛋白反应(UPR)。这项合作赠款汇集了我们过去的工作和新的初步数据，以完成这一图景。我们假设NRF在神经元中起作用，传递有关饮食的信息，并调节肠道中的UPR激活。这一系列事件将控制营养调节的摄食行为、新陈代谢和与年龄相关的健康。这里提出的工作将使用线虫秀丽线虫来研究这两个途径之间的大脑-肠道关系。蠕虫是这方面的完美选择，因为它带有现成的遗传工具箱，包括：让我们研究特定基因/分子功能的突变体；让我们看到分子何时何地开启或关闭的荧光记者；以及一个完全映射的神经系统，这样我们就可以准确地知道哪些神经元相互发送信号。这个有用且经济高效的模型将使我们能够建立从食物感觉到神经元NRF信号再到UPR激活的分子序列。此外，这些微小的动物是饮食行为、与年龄相关的健康和寿命的极好模型，使我们能够探索分子变化对这些过程的影响。确定将营养信息与新陈代谢健康和衰老的影响联系起来的分子机制，将有助于开发利用这些机制或针对其特定分子功能的疗法，以便从治疗上操纵衰老和健康，为延缓和治疗饮食引起的疾病和其他与年龄有关的非传染性疾病提供途径。