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

基本信息

  • 批准号:
    MR/Y013395/1
  • 负责人:
  • 金额:
    $ 371.49万
  • 依托单位:
  • 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

项目摘要

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细胞,对人体免疫系统至关重要。我们之所以知道这一点,部分是因为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年代末骨髓移植技术发展之前,它一直被视为死刑。如今,干细胞移植可以挽救大多数这些孩子,只要他们的病情在感染发生之前被识别出来。出于这个原因,我们现在开始对新生儿进行SCID筛查,使用一种测试,同时对一周大时已经收集的干血点进行其他筛查。如果T细胞数量低,婴儿会接受进一步的检测和治疗,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存在拼写错误。由DNA组成的基因提供了制造单个蛋白质的指令。在SCID中,单个基因的错误意味着T细胞缺少了一种不可或缺的蛋白质。结果,T细胞不能正常发育,导致免疫系统衰竭。科学家们通过研究这一过程可能出错的多种方式,对健康T细胞是如何发育的有了很多了解。事实证明,许多不同基因的拼写错误可以阻止T细胞的发育。部分原因是T细胞以如此惊人的方式发育!确切地知道是哪个基因出错导致了新的SCID病例是非常有帮助的。它指导病人的治疗方式,而且,它使预测家庭中未来怀孕的风险成为可能。有时,科学家已经能够设计出不需要干细胞移植就能替代缺失部分的方法,例如在某些情况下通过基因治疗或酶替代。这些聪明的治疗依赖于确切地知道哪个基因出了问题,因为那是需要被替换的基因。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,我们将试图弄清为什么T细胞在那里发育失败,以及我们可能对此能做些什么。其中一些患者可能在“旧的”SCID基因中有新的拼写错误,可能隐藏在有能力关闭邻近基因的DNA部分中。为了让我们有更好的机会找到这些,我们将使用新的和强大的方法来读取DNA分子,更广泛地观察每个SCID基因,并检查患者骨髓细胞中的基因是否开启或关闭。还有一些患者的新基因会出现拼写错误,而这些新基因以前与SCID没有关联——它们不在任何教科书的列表中。通过筛选过去SCID患者的拼写错误,我们已经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,我们将在试管中研究细胞中的每个拼写错误,并找出它是如何扰乱相关蛋白质的结构和功能的。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SCID。如果我们能确定这些事情,我们就会了解到关于T细胞如何工作的一些新的和重要的东西。我们应该能更好地在未来的婴儿身上诊断出同样类型的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更好的方法来挽救T细胞的发育,而不需要干细胞移植。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Sophie Hambleton其他文献

Human dendritic cell deficiency: the missing ID?
人类树突状细胞缺陷:缺失的识别码?
  • DOI:
    10.1038/nri3046
  • 发表时间:
    2011-08-19
  • 期刊:
  • 影响因子:
    60.900
  • 作者:
    Matthew Collin;Venetia Bigley;Muzlifah Haniffa;Sophie Hambleton
  • 通讯作者:
    Sophie Hambleton
Inborn errors of immunity reveal molecular requirements for generation and maintenance of human CD4sup+/sup IL-9–expressing cells
先天性免疫缺陷揭示了人类表达白细胞介素-9(IL-9)的CD4⁺细胞生成和维持的分子需求
  • DOI:
    10.1016/j.jaci.2024.11.031
  • 发表时间:
    2025-04-01
  • 期刊:
  • 影响因子:
    11.200
  • 作者:
    Geetha Rao;Corinne D. Mack;Tina Nguyen;Natalie Wong;Kathryn Payne;Lisa Worley;Paul E. Gray;Melanie Wong;Peter Hsu;Michael O. Stormon;Kahn Preece;Daniel Suan;Michael O’Sullivan;Annaliesse K. Blincoe;Jan Sinclair;Satoshi Okada;Sophie Hambleton;Peter D. Arkwright;Kaan Boztug;Polina Stepensky;Cindy S. Ma
  • 通讯作者:
    Cindy S. Ma
Allogeneic Stem Cell Transplant Offers Cure for Intractable Childhood Enteropathy
  • DOI:
    10.1016/j.bbmt.2013.12.113
  • 发表时间:
    2014-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    Austen J.J. Worth;Zohreh Nademi;Jochen Kammermeier;Su Bunn;Robert Chiesa;Andrew Cant;Sophie Hambleton;Neil Shah;Mary Slatter;Kanchan Rao;Andrew Gennery;Mamoun Elawad;Persis Amrolia;Paul Veys
  • 通讯作者:
    Paul Veys
A child with recurrent mycobacterial infection
  • DOI:
    10.1016/j.jinf.2007.04.038
  • 发表时间:
    2007-09-01
  • 期刊:
  • 影响因子:
  • 作者:
    Anoop S. Pulickal;Sophie Hambleton;Martin J. Callaghan;Catrin E. Moore;Jon Goulding;Anna Goodsall;Richard Baretto;David A. Lammas;Suzanne T. Anderson;Michael Levin;Andrew J. Pollard
  • 通讯作者:
    Andrew J. Pollard
Rare disease gene association discovery in the 100,000 Genomes Project
10 万基因组计划中的罕见病基因关联发现
  • DOI:
    10.1038/s41586-025-08623-w
  • 发表时间:
    2025-02-26
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Valentina Cipriani;Letizia Vestito;Emma F. Magavern;Julius O. B. Jacobsen;Gavin Arno;Elijah R. Behr;Katherine A. Benson;Marta Bertoli;Detlef Bockenhauer;Michael R. Bowl;Kate Burley;Li F. Chan;Patrick Chinnery;Peter J. Conlon;Marcos A. Costa;Alice E. Davidson;Sally J. Dawson;Elhussein A. E. Elhassan;Sarah E. Flanagan;Marta Futema;Daniel P. Gale;Sonia García-Ruiz;Cecilia Gonzalez Corcia;Helen R. Griffin;Sophie Hambleton;Amy R. Hicks;Henry Houlden;Richard S. Houlston;Sarah A. Howles;Robert Kleta;Iris Lekkerkerker;Siying Lin;Petra Liskova;Hannah H. Mitchison;Heba Morsy;Andrew D. Mumford;William G. Newman;Ruxandra Neatu;Edel A. O’Toole;Albert C. M. Ong;Alistair T. Pagnamenta;Shamima Rahman;Neil Rajan;Peter N. Robinson;Mina Ryten;Omid Sadeghi-Alavijeh;John A. Sayer;Claire L. Shovlin;Jenny C. Taylor;Omri Teltsh;Ian Tomlinson;Arianna Tucci;Clare Turnbull;Albertien M. van Eerde;James S. Ware;Laura M. Watts;Andrew R. Webster;Sarah K. Westbury;Sean L. Zheng;Mark Caulfield;Damian Smedley
  • 通讯作者:
    Damian Smedley

Sophie Hambleton的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Sophie Hambleton', 18)}}的其他基金

Cellular drivers of type I interferon-mediated neuropathology
I 型干扰素介导的神经病理学的细胞驱动因素
  • 批准号:
    MR/Y001958/1
  • 财政年份:
    2023
  • 资助金额:
    $ 371.49万
  • 项目类别:
    Research Grant
Memory T cells to improve immunity after TCRab/CD19 depleted haploidentical donor stem cell transplantation for inborn errors of immunity
TCRab/CD19 耗尽的单倍相合供体干细胞移植治疗先天性免疫缺陷后,记忆 T 细胞可提高免疫力
  • 批准号:
    MR/W021587/1
  • 财政年份:
    2022
  • 资助金额:
    $ 371.49万
  • 项目类别:
    Research Grant
The role of natural killer cells in host defence against varicella
自然杀伤细胞在宿主防御水痘中的作用
  • 批准号:
    G0701897/1
  • 财政年份:
    2008
  • 资助金额:
    $ 371.49万
  • 项目类别:
    Fellowship

相似海外基金

Rural Co-Design and Collaboration: Maximising Rural Community Assets to Reduce Place-Based Health Inequalities
农村共同设计与协作:最大化农村社区资产以减少基于地点的健康不平等
  • 批准号:
    AH/Z505559/1
  • 财政年份:
    2024
  • 资助金额:
    $ 371.49万
  • 项目类别:
    Research Grant
Uncovering the antimicrobial and antibiotic potentiating mechanism of acesulfame-K and maximising its topical therapeutic potential.
揭示安赛蜜的抗菌和抗生素增强机制并最大限度地发挥其局部治疗潜力。
  • 批准号:
    MR/Y001354/1
  • 财政年份:
    2024
  • 资助金额:
    $ 371.49万
  • 项目类别:
    Research Grant
COEXIST-Maximising data from fragmented bone to understand the coexistence of late Neanderthals and early Homo sapiens in central and southeast Europe
共存——最大化来自碎片骨骼的数据,以了解中欧和东南欧晚期尼安德特人和早期智人的共存
  • 批准号:
    EP/Y037448/1
  • 财政年份:
    2024
  • 资助金额:
    $ 371.49万
  • 项目类别:
    Research Grant
Maximising the value of the 2021 Northern Ireland Census
最大化 2021 年北爱尔兰人口普查的价值
  • 批准号:
    ES/Z502777/1
  • 财政年份:
    2024
  • 资助金额:
    $ 371.49万
  • 项目类别:
    Research Grant
A rEVOLUTIONary approach for maximising process water REuse and REsource REcovery through a smart, circular and integrated solution (R3volution)
通过智能、循环和集成解决方案 (R3volution) 实现工艺用水再利用和资源回收最大化的革命性方法
  • 批准号:
    10110156
  • 财政年份:
    2024
  • 资助金额:
    $ 371.49万
  • 项目类别:
    EU-Funded
Cheese from Peas: Maximising Use and Nutritional Value of UK Pulses for Dairy Alternatives.
豌豆奶酪:最大限度地提高英国豆类乳制品替代品的用途和营养价值。
  • 批准号:
    10072090
  • 财政年份:
    2023
  • 资助金额:
    $ 371.49万
  • 项目类别:
    Collaborative R&D
Maximising tidal energy generation through Blade Scaling & Advanced Digital Engineering - MAXBlades
通过叶片缩放最大限度地提高潮汐能发电量
  • 批准号:
    10064409
  • 财政年份:
    2023
  • 资助金额:
    $ 371.49万
  • 项目类别:
    EU-Funded
The changing face of HIV in the era of COVID-19: Maximising HIV incidence reduction through dynamic targeting of current and future distributions of acquisition risk.
COVID-19 时代艾滋病毒的面貌不断变化:通过动态定位当前和未来的感染风险分布,最大限度地降低艾滋病毒发病率。
  • 批准号:
    10548290
  • 财政年份:
    2023
  • 资助金额:
    $ 371.49万
  • 项目类别:
Community-led storytelling for Corporate Social Responsibility campaigns: centering communities experiences and maximising impact.
以社区为主导的企业社会责任活动故事讲述:以社区经验为中心并最大限度地发挥影响力。
  • 批准号:
    AH/Y005600/1
  • 财政年份:
    2023
  • 资助金额:
    $ 371.49万
  • 项目类别:
    Research Grant
Maximising urban green infrastructure for surface water flood management: an evidence-based approach
最大限度地利用城市绿色基础设施进行地表水洪水管理:基于证据的方法
  • 批准号:
    2890284
  • 财政年份:
    2023
  • 资助金额:
    $ 371.49万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了