The role of biased agonism in the treatment of obesity

近10亿人患有肥胖症，其中包括三分之一的英国人口。肥胖的人患糖尿病、心脏病、关节问题和癌症的风险很高。对于MRC和NHS来说，肥胖是一个高度优先的领域。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，比如“胃旁路”手术，但这会导致并发症，并不是所有患者都喜欢。因此，人们对生产帮助人们减肥的药物产生了巨大的兴趣。一组被称为“GLP-1R受体激动剂”的药物最近已被批准用于减肥。它们模拟了一种天然激素(GLP-1)的作用，通过激活其在大脑中的靶点或“感受器”来减少饥饿。其他减少饥饿的荷尔蒙，包括“胰淀素”，也在研究中，作为潜在的减肥疗法。然而，这些手术都不像胃旁路手术那样有效，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，它们的行为与市场上现有的版本不同，因为它们以一种不寻常的方式激活GLP-1R，称为“偏向激动症”。偏向的GLP-1R激动剂似乎非常有希望，因为它们能产生更多的体重减轻，但更少的恶心。有趣的是，它们与以胰淀素为基础的治疗(胰淀素类似物)结合使用时也效果特别好，即使在低剂量时也能更大程度地减少饥饿。我研究的总体目的是了解为什么偏向的GLP-1R激动剂单独或与胰淀素类似物结合使用时，对减肥效果如此好。充分了解它们的作用机制将有助于将这种方法发展成更好的肥胖症治疗方法。我将回答三个主要的研究问题：1.大脑中的哪些神经元对有偏见的GLP-1R激动剂和胰淀素类似物做出反应-它们是相同的还是不同的？这将通过测量不同的GLP-1和胰淀素类似物对小鼠摄食行为和脑组织变化的影响来完成。2.神经元如何对偏向的GLP-1R激动剂和胰淀素类似物做出反应-神经元本身发生了什么，使它们能够减少饥饿？为了回答这个问题，我将制造一只转基因小鼠，其中受体本身连接了一个荧光分子，这意味着可以使用显微镜直接观察单个受体及其行为。有偏向的GLP-1R激动剂和胰淀素类似物如何与其受体发生物理作用，以及在不同人群中发现的受体结构的自然遗传差异如何影响这一点？为了做到这一点，我将开发一种名为“深度突变扫描”的新技术，它允许在一次实验中测试数千种受体变异，这比基于单独测试每个变异的正常方法要快得多。这项工作将在伦敦帝国理工学院完成，但需要与英国和国际上的其他研究人员合作。这一结果将是开发新的减肥疗法的重要一步，也将表明遗传差异如何影响药物的效果，这意味着未来我们可能能够基于基因测试进行个性化治疗。实验的总体设计也应该适用于其他激素目标，这意味着它可以在未来开发其他肥胖治疗方法。

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.