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）是对人免疫系统至关重要的一种特殊类型的白细胞。我们知道这部分是因为不幸的婴儿出生于没有T细胞的婴儿对几乎没有影响健康儿童的感染感到非常生病。这种非常罕见的病被称为严重的免疫缺陷（“ SCID”），曾经是死刑，直到从1960年代后期开始骨髓移植的发展为止。如今，只要在感染之前就识别出病情，干细胞的移植可以节省大多数这些孩子。因此，我们现在开始使用与已经在一周大的干血点上进行的其他屏幕一起进行的测试来筛选新生婴儿的SCID。如果T细胞数量较低，婴儿将接受进一步的测试和治疗，以保护其免受感染，直到可以正确放置免疫系统为止。通常，由于我们的一个基因中的拼写错误而出生的T细胞含量低。由DNA制成的基因提供了制造单个蛋白质的说明。在SCID中，单个基因中的错误意味着T细胞缺少他们不能没有的蛋白质。结果，T细胞无法正确发展，使免疫系统耗尽。科学家已经通过研究该过程出错的多种方式来研究健康的T细胞如何发展。事实证明，许多不同基因中的拼写错误可以防止T细胞发展。这部分是因为T细胞以如此出色的方式发展！确切地知道哪个基因出现问题可能会非常有帮助。它指导患者的治疗方式和此外，可以预测家庭中未来怀孕的风险。有时，科学家已经能够设计出无需干细胞移植的无需干细胞移植的丢失部分的方法，例如在某些情况下通过基因治疗或酶替代酶。这些类型的巧妙治疗方法依赖于确切知道哪种基因出错了，因为那是需要更换的基因。那令人沮丧的是，即使使用非常现代的技术，也无法从10案例中造成十分之一的SCID案例。基因组测序。在这个研究项目中，我们将尝试达到为什么T细胞开发在那里失败以及我们对此有能力做的事情的底层。这些患者中的一些可能会在“旧” SCID基因中存在新的拼写错误，也许隐藏在具有关闭邻近基因的DNA部分中。为了使我们有一个更好的机会找到这些这些，我们将使用沿DNA分子的新和有力的读取方式更广泛地围绕每个SCID基因，并检查患者的骨髓细胞中是否打开还是关闭基因。其他患者将在新基因中遇到拼写错误，这些错误以前尚未与SCID联系在一起 - 他们不在任何教科书列表中。我们已经通过筛选过去SCID患者的拼写错误来发现一些有力的候选人。我们还有更多的工作要做，以理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具有活性。为了提供帮助，我们将研究测试管中细胞中的每个拼写错误，并找出它如何打扰相关蛋白质的结构和功能。我们还将研究同一基因中的同一拼写错误是否会导致鼠标版本的SCID。如果我们能确定这些事情，我们将学到有关T细胞如何工作的新事物和重要的东西。我们应该更好地诊断未来婴儿的SCID，并为妈妈和爸爸提供答案。我们和其他人将努力寻找新的，更好的方法来挽救T细胞的发育而没有干细胞移植。