Haematopoiesis in a Dish: From Tissue Dynamics to Molecular Mechanisms

培养皿中的造血作用：从组织动力学到分子机制

• 批准号: MR/W031663/1
• 负责人: Berthold Gottgens
• 金额: $ 100.7万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW031663%2F1
• 关键词: Haematopoiesis; Dish; Tissue; Dynamics; Molecular

In an average adult, over 2 million new blood cells are generated every second, to replace red and white blood cells lost through natural turnover and/or fighting infectious diseases. This constant replenishment is mediated by so-called stem and progenitor cells, which are long-lived, can divide to amplify their numbers, and give rise to over 10 different specialised types of blood cells. This so-called process of haematopoiesis needs to be finely balanced, because under- or overproduction of blood cells can cause severe diseases such as anaemia and leukaemia. Research at the micro-scale of individual genes and proteins has identified many regulators of haematopoiesis. It is however difficult to extrapolate from this micro-scale to the functionality of the entire blood system. Research funders have recognised this bottleneck, and therefore now prioritise research efforts aiming to connect across scales, with the expectation of accelerating both basic research as well as the drug discovery process. Here we propose to combine the latest technologies in cell culture with molecular profiling of thousands of single cells to generate a multi-scale model of blood formation, explicitly linking the micro and macro scales across time. The proposed research will develop a platform for testing the macro-scale consequences of gene mutations found in leukaemia patients, as well as the testing of new drug candidates. Moreover, establishing this platform for blood will provide a blueprint to set up analogous research efforts for other major organs and their associated diseases.

普通成年人每秒会产生超过 200 万个新血细胞，以替代因自然更新和/或对抗传染病而损失的红细胞和白细胞。这种持续的补充是由所谓的干细胞和祖细胞介导的，它们寿命长，可以分裂以扩大其数量，并产生 10 多种不同的特殊类型的血细胞。这种所谓的造血过程需要精细平衡，因为血细胞产生不足或过多会导致贫血和白血病等严重疾病。对单个基因和蛋白质的微观尺度的研究已经确定了许多造血调节因子。然而，很难从这种微观尺度推断整个血液系统的功能。研究资助者已经认识到这一瓶颈，因此现在优先考虑旨在跨尺度连接的研究工作，期望加速基础研究和药物发现过程。在这里，我们建议将细胞培养的最新技术与数千个单细胞的分子分析相结合，生成血液形成的多尺度模型，将微观和宏观尺度在时间上明确地联系起来。拟议的研究将开发一个平台，用于测试白血病患者中发现的基因突变的宏观后果，以及测试新的候选药物。此外，建立这个血液平台将为其他主要器官及其相关疾病的类似研究工作提供蓝图。

项目成果

A time- and single-cell-resolved model of murine bone marrow hematopoiesis.

小鼠骨髓造血的时间和单细胞分辨模型。

• DOI: http://dx.10.17863/cam.105533
• 发表时间: 2024
• 作者: Kucinski I

A time- and single-cell-resolved model of murine bone marrow hematopoiesis.

小鼠骨髓造血的时间和单细胞分辨模型。

• DOI: 10.1016/j.stem.2023.12.001
• 发表时间: 2023-12-29
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: I. Kucinski;Joana Campos;Melania Barile;Francesco Severi;Natacha Bohin;Pedro N. Moreira;Lewis Allen
• 通讯作者: Lewis Allen