Hierarchical organization of haematopoietic stem- and progenitor cell populations during steady state and stress haematopoiesis

稳态和应激造血过程中造血干细胞和祖细胞群的层次结构

• 批准号: MC_UU_00029/9
• 负责人: Claus Nerlov
• 金额: $ 469.92万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MC_UU_00029%2F9
• 关键词: Hierarchical; organization; haematopoietic; stem; progenitor

Normal blood cell production occurs in the bone marrow and deteriorates during ageing and is impaired by blood cancer development. In this program we will study how normal blood cell production is regulated, and in particular how regulatory genes form interlinked networks that allow the many different blood cell cell types to be generated from a single stem cell. We will use this knowledge to investigate how blood cell production is perturbed in clonal hematopoiesis (CH – a preleukemic syndrome) and myelofibrosis (MF – a hyperproliferative disorder that leads to bone marrow failure). For this purpose, we will design and develop new genetic mouse models that accurately replicate the genetic events that cause CH and MF in humans. As both CH and MF occurs more frequently in the elderly, we will use these models to to identify the physiological changes that occur during ageing that contribute to perturbation of the normal regulatory networks within hematopoietic stem cells and lead to disease development. The identified molecules or cell types will then be targeted with appropriate drugs (which will be developed in necessary) for their ability to counteract disease development. In this manner we hope to develop new therapeutic strategies for these blood disorders.

正常的血细胞生成发生在骨髓中，并随着衰老而退化，并因血癌的发展而受损。在这个项目中，我们将研究如何调节正常的血细胞生成，特别是调节基因如何形成相互关联的网络，从而允许从单个干细胞生成许多不同的血细胞类型。我们将利用这些知识来研究克隆造血（CH - 一种白血病前期综合征）和骨髓纤维化（MF - 一种导致骨髓衰竭的过度增殖性疾病）中血细胞生成如何受到干扰。为此，我们将设计和开发新的基因小鼠模型，以准确复制导致人类 CH 和 MF 的基因事件。由于 CH 和 MF 在老年人中更常见，我们将使用这些模型来识别衰老过程中发生的生理变化，这些变化会扰乱造血干细胞内的正常调节网络并导致疾病的发展。然后，将针对已识别的分子或细胞类型使用适当的药物（将在必要时开发），以使其具有抵抗疾病发展的能力。通过这种方式，我们希望为这些血液疾病开发新的治疗策略。

项目成果

Panhematopoietic RNA barcoding enables kinetic measurements of nucleate and anucleate lineages and the activation of myeloid clones following acute platelet depletion.

• DOI: 10.1186/s13059-023-02976-z
• 发表时间: 2023-06-27
• 期刊: Genome biology
• 影响因子: 12.3

Perivascular niche cells sense thrombocytopenia and activate hematopoietic stem cells in an IL-1 dependent manner.

• DOI: 10.1038/s41467-023-41691-y
• 发表时间: 2023-09-28
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Luis, Tiago C.;Barkas, Nikolaos;Carrelha, Joana;Giustacchini, Alice;Mazzi, Stefania;Norfo, Ruggiero;Wu, Bishan;Aliouat, Affaf;Guerrero, Jose A.;Rodriguez-Meira, Alba;Bouriez-Jones, Tiphaine;Macaulay, Iain C.;Jasztal, Maria;Zhu, Guangheng;Ni, Heyu;Robson, Matthew J.;Blakely, Randy D.;Mead, Adam J.;Nerlov, Claus;Ghevaert, Cedric;Jacobsen, Sten Eirik W.
• 通讯作者: Jacobsen, Sten Eirik W.

DNMT1 Deficiency Impacts on Plasmacytoid Dendritic Cells in Homeostasis and Autoimmune Disease.

• DOI: 10.4049/jimmunol.2100624
• 发表时间: 2022-01-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Czeh M;Stäble S;Krämer S;Tepe L;Talyan S;Carrelha J;Meng Y;Heitplatz B;Schwabenland M;Milsom MD;Plass C;Prinz M;Schlesner M;Andrade-Navarro MA;Nerlov C;Jacobsen SEW;Lipka DB;Rosenbauer F
• 通讯作者: Rosenbauer F