The role of biased agonism in the treatment of obesity

偏向激动在肥胖治疗中的作用

• 批准号: MR/Y00132X/1
• 负责人: Ben Jones
• 金额: $ 226.57万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY00132X%2F1
• 关键词: role; biased; agonism; treatment; obesity

Almost one billion people are obese, including one third of the UK population. People who are obese are at high risk of developing diabetes, heart disease, joint problems and cancer. Obesity is an area of high priority for the MRC and for the NHS. Many people find it difficult to lose weight naturally. The only truly effective treatment is weight loss surgery, such as the "gastric bypass" operation, but this can lead to complications and is not popular with all patients. As a result, there is enormous interest in producing medicines to help people lose weight. A group of medicines known as "glucagon-like peptide-1 receptor (GLP-1R) agonists" has recently been approved for weight loss. These mimic the effect of a natural hormone (GLP-1) by activating its target, or "receptor", in the brain to reduce hunger. Other hunger-reducing hormones, including "amylin", are also under investigation as potential weight loss treatments. However, none of these are as effective as gastric bypass surgery because the maximum dose is limited by nausea and/or vomiting. I have recently generated new, improved GLP-1R agonists that behave differently to existing versions on the market as they activate GLP-1R in an unusual way, referred to as "biased agonism". Biased GLP-1R agonists appear very promising as they produce more weight loss but less nausea. Interestingly, they also work particularly well in combination with amylin-based treatments (amylin analogues), causing larger reductions in hunger even at low doses.The overall aim of my research is to understand why biased GLP-1R agonists work so well for weight loss, both on their own and when combined with with amylin analogues. Fully understanding their mechanism of action will help develop this approach into a better treatment for obesity. I will address three main research questions: 1. Which neurons in the brain respond to biased GLP-1R agonists and amylin analogues - are they the same or different? This will be done by measuring the effect of different GLP-1 and amylin analogues on feeding behaviour and changes to brain tissue in mice. 2. How do neurons respond to biased GLP-1R agonists and amylin analogues - what is happening inside the neurons themselves that allows them to reduce hunger? To answer this, I will generate a genetically modified mouse in which the receptor itself has a fluorescent molecule attached, meaning individual receptors and how they behave can be directly observed using a microscope.3. How do biased GLP-1R agonists and amylin analogues physically interact with their receptors, and how is this affected by natural genetic variations in receptor structure found in different people? To do this I will develop a new technique called "deep mutational scanning", which allows thousands of receptor variations to be tested in in a single experiment, which is much faster than the normal method based on testing each variation individually.This work will be done at Imperial College London but involve collaborations with other researchers in the UK and internationally. The results will be an important step to developing a new weight loss treatment, and will also show how genetic differences can influence how well the drugs work, meaning that in the future we may be able to individualise treatments based on genetic testing.The overall design of the experiments should also be applicable to other hormone targets, meaning it could be used to develop other obesity treatments in the future.

将近十亿人肥胖，其中包括英国人口的三分之一。肥胖的人患糖尿病，心脏病，关节疾病和癌症的高风险。肥胖是MRC和NHS优先级的一个领域。许多人发现很难自然减肥。唯一真正有效的治疗方法是减肥手术，例如“胃旁路”手术，但这可能导致并发症，并且并不受到所有患者的欢迎。结果，生产药物以帮助人们减肥的兴趣很大。最近已批准了一组称为“胰高血糖素样肽1受体（GLP-1R）激动剂”的药物。这些模仿天然激素（GLP-1）通过在大脑中激活其靶标或“受体”以减少饥饿感的效果。其他减少饥饿的激素，包括“淀粉纤维”，也正在接受潜在的减肥治疗。但是，这些都没有像胃搭桥手术那样有效，因为最大剂量受到恶心和/或呕吐的限制。我最近产生了新的，改进的GLP-1R激动剂，这些激动剂的行为与市场上的现有版本不同，因为它们以一种不寻常的方式激活GLP-1R，被称为“偏见激动”。偏见的GLP-1R激动剂似乎非常有前途，因为它们会产生更多的体重减轻，但恶心却更少。有趣的是，它们在与基于Amylin的治疗（淀粉蛋白酶类似物）结合使用方面也特别好，即使在低剂量下也会导致饥饿感更大。我的研究的总体目的是了解为什么偏见的GLP-1R激动剂偏向于减肥，既可以自行减肥，又与淀粉纤维组合时。充分了解他们的作用机制将有助于将这种方法发展为更好的肥胖治疗方法。我将解决三个主要的研究问题：1。大脑中哪些神经元对偏见的GLP -1R激动剂和淀粉纤维类似物反应 - 它们是相同还是不同？这将通过测量不同的GLP-1和淀粉蛋白酶对小鼠的喂养行为以及对脑组织的变化的影响来完成。 2。神经元如何应对偏见的GLP -1R激动剂和氨基蛋白类似物 - 神经元本身中发生了什么，使它们减少了饥饿？为了回答这一点，我将生成一种遗传修饰的小鼠，其中受体本身具有附着的荧光分子，这意味着单个受体以及如何使用显微镜直接观察它们。3。偏见的GLP-1R激动剂和淀粉蛋白类似物如何与其受体进行物理相互作用，以及在不同人中发现的受体结构自然遗传变异的影响如何？为此，我将开发一种称为“深突变扫描”的新技术，该技术允许在一个实验中对数千种受体变化进行测试，该实验比单独测试每个变化的正常方法要快得多。这项工作将在伦敦帝国学院进行，但涉及英国和国际的其他研究人员。结果将是开发新的减肥治疗方法的重要步骤，还将显示遗传差异如何影响药物的工作状况，这意味着将来我们可能能够基于基因测试来个性化治疗。