MICA: A platform to support the pharmacological targeting of Nrf2 in humans

当体内有害自由基和保护性抗氧化剂之间存在不平衡时，就会引起氧化应激。它与许多形式的人类疾病有关。正常情况下，细胞通过增加Nrf2的活性来应对氧化应激，Nrf2是一种控制200多种保护性基因表达的蛋白质。其中一些基因帮助我们的细胞产生更多的抗氧化剂，清除有害的自由基。这降低了体内的氧化应激水平。大量临床前研究表明，激活Nrf2在不同类型的疾病中具有有益作用。此外，少数刺激Nrf2的药物最近已进入临床试验阶段。尽管取得了这些令人兴奋的进展，但仍有两个关键的知识空白阻碍我们在某些临床环境中有效地使用Nrf2激活药物，即：1。对于使用Nrf2激活药物来治疗已知会增加患者患癌症风险的疾病是否会进一步促进肿瘤形成，目前还不确定。这与在多种癌症中检测到高水平的Nrf2活性有关。2. 缺乏对使用血液等样本监测Nrf2对药物刺激反应的最佳方法的认识。这很重要，因为我们需要方法来确认一种药物是否刺激了Nrf2，以便将其与对疾病的任何积极影响联系起来。这将帮助我们确认用药物刺激Nrf2对患者来说是一个很好的策略。该研究的目的是利用最先进的细胞、动物和临床方法来解决这些知识空白，并提供证据支持Nrf2刺激作为治疗与氧化应激相关的人类疾病的新方法。这种疾病的一个很好的例子是一种影响英国500多万成年人的脂肪肝疾病，目前尚无任何批准的治疗方法。Nrf2正在显示出作为一种新的治疗靶点的希望。重要的是，高达20%的患者会发展为原发性肝癌。在这个项目中，我将通过测试一种刺激Nrf2的药物是可以改善脂肪肝疾病，抑制原发性肝癌的发展，还是会使原发性肝癌的发展恶化，来解决第一个知识缺口。我将测试在脂肪肝疾病的早期或晚期开始使用该药治疗是否会影响这些结果的平衡。这一发现对其他疾病也很重要，其中Nrf2似乎是一个有希望的新药靶点。其中包括与氧化应激有关的某些肺部和肾脏疾病，但这些疾病也与患癌症的风险增加有关。我将通过测量患者和服用刺激Nrf2药物的健康志愿者血液样本中所有基因和蛋白质的变化来解决第二个知识缺口。我将寻找与正常水平相比，对药物反应变化最大的基因/蛋白质水平，因为这些可能是Nrf2反应的标志，在服用其他Nrf2激活药物的患者中会发生变化。从长远来看，我们将能够在测量这些基因/蛋白质的基础上开发出Nrf2反应的特异性测试，并利用这些测试更好地解释Nrf2激活药物对患者的治疗效果。总的来说，这项研究将提高我们对使用药物刺激患者Nrf2的益处和风险的理解，并增强我们在临床监测治疗反应的能力。这将支持开发针对不同形式疾病的新药。

Oxidative stress is caused when there is an imbalance between harmful free radicals and protective antioxidants in the body. It is linked to many forms of human disease. Normally, cells respond to oxidative stress by increasing the activity of Nrf2, a protein that controls the expression of over 200 protective genes. Some of these genes help our cells to make more antioxidants and remove the harmful free radicals. This lowers levels of oxidative stress in the body. A large number of preclinical studies have shown a beneficial role of activating Nrf2 in different types of disease. In addition, a small number of drugs that stimulate Nrf2 have recently entered clinical trials. Despite these exciting advances, there remain two key knowledge gaps that prevent us from using Nrf2 activating drugs effectively in certain clinical settings, namely:1. An uncertainty around whether using Nrf2 activating drugs to treat diseases that are known to increase a patient's risk of developing cancer could further promote tumour formation. This is linked to the fact that high levels of Nrf2 activity have been detected in many forms of cancer. 2. A lack of awareness about the best way to monitor the response of Nrf2 to drug stimulation in patients using samples such as blood. This is important as we need ways to confirm that a drug has stimulated Nrf2 in order to link this to any positive effects on a disease. This will help us to confirm that stimulating Nrf2 with drugs is a good strategy in patients. The aim of this fellowship is to use state-of-the-art cell, animal and clinical approaches to address these knowledge gaps and provide evidence to support the stimulation of Nrf2 as a novel approach to treating human diseases associated with oxidative stress. A good example of such a disease, and one in which Nrf2 is showing promise as a novel therapeutic target, is a form of fatty liver disease that affects over 5 million adults in the UK and currently lacks any approved therapies. Importantly, up to 20 % of patients with this disease will go on to develop primary liver cancer. In this fellowship, I will tackle the first knowledge gap by testing whether a drug that stimulates Nrf2 can improve the fatty liver disease and inhibit the development of primary liver cancer, or whether it can make the development of primary liver cancer worse. I will test whether the balance of these outcomes is affected by whether treatment with the drug is started in the early or advanced stages of fatty liver disease. The findings will also be important for other diseases in which Nrf2 appears to be a promising new drug target. These include certain lung and kidney conditions that involve oxidative stress, but which are also linked to an increased risk of developing cancer. I will tackle the second knowledge gap by measuring changes in all genes and proteins in samples of blood from patients and healthy volunteers taking drugs that stimulate Nrf2. I will look for gene/protein levels that change the most in response to the drugs when compared to normal levels, as these are likely to be markers of the Nrf2 response that will change in patients taking other Nrf2 activating drugs. In the long term, we will be able to develop specific tests of the Nrf2 response based on the measurement of these genes/proteins, and use these tests to better interpret the therapeutic effects of Nrf2 activating drugs in patients. Overall, this fellowship will improve our understanding of the benefits and risks of using drugs to stimulate Nrf2 in patients, and enhance our ability to monitor therapeutic responses in the clinic. This will support the development of new medicines in different forms of disease.