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MICA: Identification of compounds capable of de-repressing zeta-globin in order to treat patients with severe alpha-thalassaemia

MICA：鉴定能够解除 zeta 珠蛋白抑制的化合物，以治疗严重 α 地中海贫血患者

基本信息

批准号：
MC_EX_MR/R023301/1
负责人：
Douglas Higgs
金额：
$ 1.14万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MC_EX_MR%2FR023301%2F1
关键词：
MICA Identification compounds capable de

项目摘要

Haemoglobin (Hb) is the major component of the protein found in red blood cells, it gives blood its red colour and is responsible for carrying oxygen around the body. Haemoglobin is made up of four chains: 2 alpha chains and 2 beta chains. Mutations in the genetic code (the DNA) responsible for producing these chains can lead to decreased production of the alpha chains, a condition called alpha-thalassaemia (mutation of the beta-chains, causes beta-thalassemia). There are four alpha-globin genes in humans, each of which normally contributes to alpha-globin production. If one or two genes are affected by mutations, then this produces a mild anaemia without any symptoms. However, if three alpha-globin genes are affected, this can lead to a severe anaemia needing regular transfusions. If all four alpha-globin genes are affected, this means that no functional haemoglobin can be produced, and such patients die in the womb approximately 4-6 months after conception (a condition called Barts Hydrops fetalis). Mild alpha-thalassaemia provides some protection against the infectious disease malaria. In certain parts of the world, alpha-thalassaemia is therefore very common: the carrier frequency is 4-8% in Southern China and Hong Kong and at a similar level in the Thai, Filipino and Vietnamese populations, however, it is most common in Northern Thailand where up to 14% of the population are carriers. Severe alpha-thalassemia is therefore a major global health problem with at least 26,000 at-risk pregnancies annually and because of migration this is now a global health problem. At the moment, treatments for alpha-thalassaemia are limited to blood transfusion and occasionally, bone marrow transplantation. Bone marrow transplantation can be very dangerous, with up to 1/5 patients dying because of the procedure itself. Regular blood transfusions also cause serious medical problems long-term. In addition, it is normally recommended that Bart's Hydrops fetalis babies are aborted because they are so unwell prior to being born. We therefore urgently need new treatments for severe forms of alpha-thalssaemia. When babies develop, they initially produce a different globin chain, similar to alpha-globin for the first 8 weeks after conception; this is called zeta-globin. We know this is capable of substituting for alpha-globin in adults. Unfortunately however, it is normally switched off after eight weeks. If we could find a way of turning it back on in adult red blood cells, this would treat patients with severe forms of alpha-thalssaemia and could allow them to live a normal life.In this project, we aim to identify chemical compounds which could be used as medicines to switch zeta-globin back on, thereby treating patients with severe alpha-thalassaemia. To help undertake this, we have made a mouse, where zeta-globin is "tagged" by a fluorescent protein. This means that we have a sensitive and specific way of identifying blood cells where zeta-globin is turned on, as when zeta-globin is on, the red blood cell glows. This allows us to add lots of different compounds to red blood cells from the mouse, and see quickly and easily which ones cause the red blood cells to glow. Once we have identified potential compounds, we will make sure they also turn zeta-globin back on in human cells and try and understand how they are turning zeta-globin back on by doing additional experiments. We will perform the initial screen of compounds by collaborating with a pharmaceutical company called AstraZeneca, as they have particular expertise in developing medicines. Longer-term, we would aim to test the compounds, initially in mouse models of alpha-thalassaemia, then in human cellular systems and if that is successful, in people.

血红蛋白（Hb）是红细胞中蛋白质的主要成分，它使血液呈红色，并负责将氧气输送到全身。血红蛋白由四条链组成：两条α链和两条β链。负责产生这些链的遗传密码（DNA）的突变可导致α链的产生减少，这种情况称为α -地中海贫血（β链的突变导致β -地中海贫血）。人类有四种α -珠蛋白基因，每一种基因通常都有助于α -珠蛋白的产生。如果一个或两个基因受到突变的影响，那么就会产生没有任何症状的轻度贫血。然而，如果三个α -珠蛋白基因受到影响，这可能导致严重的贫血，需要定期输血。如果所有四种α -珠蛋白基因都受到影响，这意味着不能产生功能性血红蛋白，这样的患者在怀孕后大约4-6个月就会在子宫内死亡（这种情况称为巴氏水肿胎儿）。轻度α -地中海贫血症对传染性疾病疟疾提供了一些保护。因此，在世界某些地区，α -地中海贫血非常普遍：中国南方和香港的携带者频率为4-8%，在泰国、菲律宾和越南人群中也有类似的水平，然而，在泰国北部最常见，高达14%的人口是携带者。因此，严重地中海贫血是一个重大的全球健康问题，每年至少有26 000人面临怀孕风险，由于移徙，这现已成为一个全球健康问题。目前，对地中海贫血的治疗仅限于输血，偶尔也需要骨髓移植。骨髓移植可能非常危险，多达五分之一的患者因手术本身而死亡。长期定期输血也会导致严重的医疗问题。此外，通常建议巴特氏水肿胎儿流产，因为他们在出生前就很不舒服。因此，我们迫切需要针对严重形式的α -地中海贫血的新疗法。当婴儿发育时，他们最初产生不同的珠蛋白链，在怀孕后的前8周类似于α -珠蛋白；这被称为泽塔珠蛋白。我们知道它可以替代成人体内的α -珠蛋白。然而，不幸的是，它通常在八周后关闭。如果我们能找到一种方法，使成人红细胞中的α -地中海贫血恢复正常，这将治疗患有严重α -地中海贫血的患者，并使他们过上正常的生活。在这个项目中，我们的目标是确定可以用作药物的化合物来重新启动ζ -珠蛋白，从而治疗严重的α -地中海贫血患者。为了帮助完成这项工作，我们制造了一只老鼠，其中的泽塔珠蛋白被荧光蛋白“标记”。这意味着我们有一种敏感而特异的方法来识别细胞，当ζ珠蛋白被激活时，红细胞就会发光。这使我们能够向小鼠的红细胞中添加许多不同的化合物，并快速而容易地看到哪些化合物导致红细胞发光。一旦我们确定了潜在的化合物，我们将确保它们也能在人体细胞中激活ζ -珠蛋白，并试图通过进行额外的实验来了解它们是如何激活ζ -珠蛋白的。我们将与阿斯利康制药公司合作进行化合物的初步筛选，因为他们在开发药物方面具有特殊的专业知识。从长远来看，我们的目标是测试这些化合物，首先在患有地中海贫血的小鼠模型中进行测试，然后在人体细胞系统中进行测试，如果成功的话，将在人体中进行测试。