The Oxford Single Cell Biology Consortium

牛津单细胞生物学联盟

• 批准号: MR/M00919X/1
• 负责人: Douglas Higgs
• 金额: $ 633.97万
• 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: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM00919X%2F1
• 关键词: Oxford; Single; Cell; Biology; Consortium

Limitations in our ability to study the biology of individual cells has historically been a major obstacle, inhibiting our understanding of some fundamental problems in biomedical research such as the onset of cancer, the immunological determination of 'self', and the ability to purify tissue-specific stem cells. Recent developments in the field of single cell genomics is now opening up unprecedented opportunities to uncover individual cell differences within such complex tissues. The objective of the proposed research is to establish a Centre of Single Cell Biology (CSCB) in Oxford that will take advantage of this pioneering technology in order to improve the diagnosis, stratification and treatment of a wide variety of human diseases. The CSCB will be coordinated by the Weatherall Institute of Molecular Medicine (WIMM) which has a long-standing technical and strategic expertise in single cell research. The capital development will be used to enhance single-cell research capabilities across the campus in a number of key areas:Data analysis: Single cell genomics studies generate an enormous amount of data, with consequent challenges for the analysis and correct interpretation of these complex data sets. We propose to establish an entirely new research group devoted to the development of novel approaches for the statistical and computational analysis of single cell biology data and its application to medicine. This group will be located in new space to be developed at the WIMM, but jointly led by leading scientists across the campus. This new initiative will provide a clear pathway to integrate multidisciplinary, scientific and technical innovation in single cell biology research across the Oxford University Campus and to provide ground-breaking applications of this approach to medicine in the UK.State of the art facilities: We will develop single cell biology research laboratories to allow practical access for research groups conducting these studies across the campus. These facilities will house cutting edge technology platforms and, importantly, will create "ultra clean" environments to carry out single cell experiments. This is necessary as very low levels of background "contamination" make the interpretation of single cell experiments challenging. Projects: As a specific example of how this technology will be applied to address fundamental problems in human disease, the lead programme of research in the CSCB will be focused on inherited disorders of red blood cells. These disorders are amongst the most common of all human genetic diseases worldwide with an estimated 300,000 affected babies born each year and a total number of affected UK patients of ~16,000. Currently, severely affected individuals are treated with supportive care, including lifelong blood transfusion and treatment to prevent accumulation of iron in the body, which is costly, burdensome, and gives rise to serious, long-term clinical complications. Here we propose to "genetically repair" the damaged genes in the patient's own blood stem cells. Single cell biology will be central to this project: First, single cell genomic approaches will be used to identify the blood stem cells which are the best target for this therapy. Second, single-cell analysis will be used to assess the safety and efficiency of this approach. This programme, focussed on developing an entirely new approach to treating the haemoglobinopathies, has the potential to transform the treatment of all human genetic diseases that can be cured by stem cell transplantation. This is one example of many projects in development across the campus which will be greatly facilitated by the development of improved single cell research capabilities.Oxford is in a very strong position to take a world-leading role in the up-and-coming area of Single Cell Biology and application of these technologies to important clinical and basic biology questions across the University and beyond.

历史上，我们研究单个细胞生物学的能力有限一直是一个主要障碍，阻碍了我们对生物医学研究中的一些基本问题的理解，如癌症的发病、自我的免疫学确定以及纯化组织特异性干细胞的能力。单细胞基因组学领域的最新发展现在为发现这种复杂组织中的单个细胞差异提供了前所未有的机会。这项拟议研究的目标是在牛津建立一个单细胞生物学中心(CSCB)，该中心将利用这项开创性的技术来改进对各种人类疾病的诊断、分层和治疗。CSCB将由韦瑟尔分子医学研究所(WIMM)协调，该研究所在单细胞研究方面拥有长期的技术和战略专长。资本开发将用于在多个关键领域加强整个校园的单细胞研究能力：数据分析：单细胞基因组学研究产生大量数据，随之而来的是对这些复杂数据集的分析和正确解释的挑战。我们建议成立一个全新的研究小组，致力于开发单细胞生物学数据的统计和计算分析及其在医学上的应用的新方法。这个小组将位于WIMM将开发的新空间，但由整个校园内的领先科学家共同领导。这一新计划将提供一条明确的途径，在牛津大学校园内整合单细胞生物学研究中的多学科、科学和技术创新，并在英国提供这种方法在医学上的开创性应用。最先进的设施：我们将发展单细胞生物学研究实验室，使整个校园内进行这些研究的研究小组能够实际接触到这些研究。这些设施将容纳尖端技术平台，重要的是，将创造进行单细胞实验的“超清洁”环境。这是必要的，因为背景污染水平非常低，使得对单细胞实验的解释具有挑战性。项目：作为如何将这项技术应用于解决人类疾病根本问题的具体例子，CSCB的主要研究计划将侧重于红细胞遗传性疾病。这些疾病是世界上最常见的人类遗传病之一，估计每年有30万名受影响的婴儿出生，英国受影响的患者总数约为1.6万人。目前，受影响严重的患者接受支持性护理，包括终身输血和防止铁在体内积聚的治疗，这是昂贵、负担沉重的，并会引起严重的长期临床并发症。在这里，我们建议从基因上修复患者自身血液干细胞中受损的基因。单细胞生物学将是该项目的核心：首先，将使用单细胞基因组方法来鉴定作为该疗法的最佳靶点的血液干细胞。其次，将使用单细胞分析来评估这种方法的安全性和有效性。这一方案的重点是开发一种治疗血红蛋白疾病的全新方法，有可能改变所有可通过干细胞移植治愈的人类遗传病的治疗方法。这是校园内许多正在开发的项目中的一个，这些项目的发展将极大地促进单细胞研究能力的发展。牛津大学处于非常有利的地位，可以在未来的单细胞生物学领域发挥世界领先的作用，并将这些技术应用于大学内外重要的临床和基础生物学问题。

项目成果

Cellular polarity modulates drug resistance in primary colorectal cancers via orientation of the multidrug resistance protein ABCB1.

• DOI: 10.1002/path.5179
• 发表时间: 2019-03
• 期刊: The Journal of pathology
• 作者: Ashley N;Ouaret D;Bodmer WF
• 通讯作者: Bodmer WF

Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors.

Ezh2 和 Runx1 突变共同引发早期胸腺祖细胞的淋巴细胞白血病。

• DOI: 10.17863/cam.22956
• 发表时间: 2018
• 作者: Booth C

A dynamic niche provides Kit ligand in a stage-specific manner to the earliest thymocyte progenitors.

• DOI: 10.1038/ncb3299
• 发表时间: 2016-02
• 期刊: Nature cell biology
• 影响因子: 21.3
• 作者: Buono M;Facchini R;Matsuoka S;Thongjuea S;Waithe D;Luis TC;Giustacchini A;Besmer P;Mead AJ;Jacobsen SE;Nerlov C
• 通讯作者: Nerlov C

Invasive Salmonella exploits divergent immune evasion strategies in infected and bystander dendritic cell subsets.

• DOI: 10.1038/s41467-018-07329-0
• 发表时间: 2018-11-19
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Aulicino A;Rue-Albrecht KC;Preciado-Llanes L;Napolitani G;Ashley N;Cribbs A;Koth J;Lagerholm BC;Ambrose T;Gordon MA;Sims D;Simmons A
• 通讯作者: Simmons A

CD34+CD19-CD22+ B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies.

• DOI: 10.1182/blood.2021014840
• 发表时间: 2022-07-07
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Bueno, Clara;Barrera, Susana;Bataller, Alex;Ortiz-Maldonado, Valentin;Elliot, Natalina;O'Byrne, Sorcha;Wang, Guanlin;Rovira, Montse;Gutierrez-Aguera, Francisco;Trincado, Juan L.;Gonzalez-Gonzalez, Maria;Morgades, Mireia;Sorigue, Marc;Barcena, Paloma;Romina Zanetti, Samanta;Torrebadell, Montse;Vega-Garcia, Nerea;Rives, Susana;Mallo, Mar;Sole, Francesc;Mead, Adam J.;Roberts, Irene;Thongjuea, Supat;Psaila, Bethan;Juan, Manel;Delgado, Julio;Urbano-Ispizua, Alvaro;Maria Ribera, Josep;Orfao, Alberto;Roy, Anindita;Menendez, Pablo
• 通讯作者: Menendez, Pablo