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.

在普通成年人中，每秒产生200多万个新的血细胞，以取代因自然周转和/或与传染病作斗争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，干细胞和祖细胞寿命很长，可以分裂以扩大自己的数量，并产生10多种不同的特殊类型的血细胞。这个所谓的造血过程需要很好的平衡，因为血细胞生产不足或过剩可能会导致严重的疾病，如贫血和白血病。对单个基因和蛋白质的微观研究已经确定了许多造血调节因子。然而，很难从这个微尺度推断出整个血液系统的功能。研究资助者已经认识到了这一瓶颈，因此现在优先考虑旨在跨规模连接的研究努力，期望同时加快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图谱相结合，以生成一个多尺度的血液形成模型，明确地将微观和宏观尺度跨越时间联系起来。这项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，以及测试新药候选药物。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提供蓝图。

项目成果

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

• DOI: 10.1016/j.stem.2023.12.001
• 发表时间: 2023-12
• 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-Lewis-All