T-max: maximising insights from severe combined immunodeficiency and related disorders

T-max：最大限度地了解严重联合免疫缺陷和相关疾病

• 批准号: MR/Y013395/1
• 负责人: Sophie Hambleton
• 金额: $ 371.49万
• 依托单位: Newcastle University
• 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=MR%2FY013395%2F1
• 关键词: max; maximising; insights; severe; combined

T lymphocytes (T cells) are a special type of white blood cell that is crucial to the human immune system. We know this partly because babies who are unlucky enough to be born without T cells get terribly sick with infections that barely affect healthy children. This very rare condition, called severe combined immunodeficiency ("SCID"), used to be a death sentence until the development of bone marrow transplantation from the late 1960s onwards. Nowadays, stem cell transplantation can save most of these children, as long as their condition is recognised before infection takes hold. For this reason, we now are starting to screen newborn babies for SCID using a test carried out alongside other screens on the dried blood spot already collected at a week of age. If T cell numbers are low, babies undergo further testing and treatment to protect them from infection until the immune system can be put right. Usually, being born with low levels of T cells happens because of spelling mistakes in one of our genes. Genes, which are made of DNA, provide the instructions to make individual proteins. In SCID, mistakes in a single gene mean that T cells are missing a protein they can't do without. As a result, the T cells can't develop properly, leaving the immune system depleted. Scientists have worked out a lot about how healthy T cells develop from studying the many ways this process can go wrong. It turns out that spelling mistakes in many different genes can prevent T cells from developing. This is partly because T cells develop in such a remarkable way! It can be very helpful to know exactly which gene has gone wrong to cause a new case of SCID. It guides the way a patient is treated and furthermore, makes it possible to predict the risk to future pregnancies within the family. Sometimes scientists have been able to design ways of replacing the missing part without a stem cell transplant, for instance by gene therapy or enzyme replacement in some cases. These types of clever treatment rely on knowing exactly which gene has gone wrong, since that is the one that needs to be replaced.It's frustrating then that around 1 in 10 cases of SCID can't be explained genetically, even using the very modern technique of genome sequencing. In this research project, we will try to get to the bottom of why T cell development fails there and what we might be able to do about it. Some of these patients might have new sorts of spelling mistakes in "old" SCID genes, perhaps hidden in parts of the DNA that have the power to turn off neighbouring genes. To give us a better chance of finding these we will look more widely around each SCID gene using new and powerful ways of reading along DNA molecules, and check whether genes are turned on or off in patient's bone marrow cells. Other patients will have spelling mistakes in new genes that haven't been linked to SCID before - they aren't on any textbook list. We have already found some strong candidates by screening for spelling mistakes in past patients with SCID. We have more work to do to understand why the affected genes are so important for T cells, because they are active in lots of other tissues too. To help, we will study each spelling mistake in cells in the test tube, and find out how it disturbs the structure and function of the related protein. We also will study whether the same spelling mistakes in the same genes can cause the mouse version of SCID. If we can be sure of these things, we will have learned something new and important about how T cells work. We should be in a better position to diagnose the same sort of SCID in future babies and provide answers to their mums and dads. We and others will be working hard to find new and better ways to rescue T cell development without a stem cell transplant.

T淋巴细胞（T细胞）是一种特殊类型的白色血细胞，对人体免疫系统至关重要。我们知道这一点的部分原因是，那些不幸出生时没有T细胞的婴儿会患上严重的感染，而这些感染对健康儿童几乎没有影响。这种非常罕见的疾病被称为严重联合免疫缺陷（“SCID”），在20世纪60年代后期骨髓移植发展之前，这种疾病曾经被判死刑。如今，干细胞移植可以挽救大多数这些儿童，只要他们的病情在感染之前得到确认。出于这个原因，我们现在开始对新生儿进行SCID筛查，使用一种与其他筛查一起进行的测试，即在一周大时收集的干血斑上进行的测试。如果T细胞数量低，婴儿需要接受进一步的测试和治疗，以保护他们免受感染，直到免疫系统恢复正常。通常，出生时T细胞水平低是因为我们的一个基因拼写错误。由DNA组成的基因提供制造单个蛋白质的指令。在SCID中，单个基因中的错误意味着T细胞缺少了一种蛋白质。因此，T细胞不能正常发育，使免疫系统衰竭。科学家们通过研究这个过程可能出错的多种方式，已经对健康的T细胞如何发育做了很多研究。事实证明，许多不同基因中的拼写错误可以阻止T细胞的发育。这部分是因为T细胞以如此惊人的方式发育！确切地知道哪个基因出了问题导致了新的SCID病例，这是非常有帮助的。它指导患者的治疗方式，此外，还可以预测家庭内未来怀孕的风险。有时，科学家已经能够设计出替代缺失部分的方法，而无需干细胞移植，例如在某些情况下通过基因治疗或酶替代。这些聪明的治疗方法依赖于准确地知道哪个基因出了问题，因为那是需要替换的基因。令人沮丧的是，即使使用非常现代的基因组测序技术，大约十分之一的SCID病例也无法从基因上解释。在这个研究项目中，我们将试图弄清楚为什么T细胞在那里发育失败，以及我们可能对此做些什么。其中一些患者可能在“旧”的SCID基因中有新的拼写错误，也许隐藏在具有关闭邻近基因能力的DNA部分中。为了让我们有更好的机会找到这些基因，我们将使用新的和强大的阅读沿着DNA分子的方法，更广泛地研究每个SCID基因，并检查基因在患者的骨髓细胞中是打开还是关闭。其他的病人会有拼写错误的新基因，这些基因以前没有与SCID联系在一起--它们没有出现在任何教科书的名单上。我们已经通过筛查过去的SCID患者的拼写错误找到了一些强有力的候选者。我们还有更多的工作要做，以了解为什么受影响的基因对T细胞如此重要，因为它们在许多其他组织中也很活跃。为了提供帮助，我们将研究试管中细胞中的每个拼写错误，并找出它如何干扰相关蛋白质的结构和功能。我们还将研究相同基因中的相同拼写错误是否会导致小鼠版本的SCID。如果我们能确定这些事情，我们将了解到T细胞如何工作的一些新的和重要的东西。我们应该能够更好地诊断出未来婴儿患上同样类型的SCID，并为他们的父母提供答案。我们和其他人将努力寻找新的和更好的方法来拯救T细胞的发展，而无需干细胞移植。