Counteracting hematopoietic ageing by pharmacological inhibition of TGFbeta and IL-6 signaling

通过药物抑制 TGFbeta 和 IL-6 信号传导来对抗造血衰老

• 批准号: MR/T015055/1
• 负责人: Claus Nerlov
• 金额: $ 56.29万
• 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: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT015055%2F1
• 关键词: Counteracting; hematopoietic; ageing; pharmacological; inhibition

Stem cells are a special type of cell with the ability to make many other types of cell. As we age, the stem cells in our bone marrow stop working properly. This means that they are no longer able to make red blood cells (the cells that transport oxygen around the body) or white blood cells (the cells that help our body fight infections), quite as efficiently. This leads to a variety of health complications, from a weak immune system that can no longer fight infections, to a reduction in cognitive and cardiovascular ability and muscle strength.The functioning of any cell in our bodies, including bone marrow stem cells, depends on how their DNA is controlled. All cells have the same DNA code in them, but read this code in different ways. The code is divided into portions of information, like words in a sentence, called genes. Each gene tells the cell to do a different task, or make a different important component.To understand why ageing has this effect, in a previous project we compared the genes are turned on and off in bone marrow stem cells obtained from young and old mice. We discovered that there are two sets of genes that seem to be more active in old bone marrow stem cells. To check that these genes were really important, we looked at the 'production' line of cell components that they code for. We found that if we tampered with these production lines, we were able to revert some of the age-related effects in the bone marrow cells.In this project, we want to understand better how we can adjust these production lines to really revert the effects of ageing in bone marrow stem cells. In particular, we want to understand how tampering with one of these production lines (known as TGFbeta signalling pathway) can lead to an increased production of white blood cells and better protection against infections. We are also interested in understanding how tampering with both production pathways can increase the production of red blood cells.Ultimately, we hope that by understanding better how these two production lines interfere with the normal work of bone marrow stem cells, we may be able to devise ways to reverse it, and hopefully help patients affected by these conditions.

干细胞是一种特殊类型的细胞，具有制造许多其他类型细胞的能力。随着年龄的增长，我们骨髓中的干细胞停止正常工作。这意味着它们不再能够以同样的效率制造红细胞(在身体周围输送氧气的细胞)或白细胞(帮助我们的身体对抗感染的细胞)。这会导致各种健康并发症，从免疫系统薄弱，不再能抵抗感染，到认知和心血管能力以及肌肉力量的下降。我们体内的任何细胞，包括骨髓干细胞，其功能都取决于它们的DNA是如何控制的。所有细胞都有相同的DNA密码，但以不同的方式阅读该密码。密码被分成信息的几个部分，就像句子中的单词一样，被称为基因。每个基因告诉细胞做不同的任务，或者制造不同的重要组成部分。为了理解为什么衰老会有这种影响，在之前的一个项目中，我们比较了从幼鼠和老年鼠获得的骨髓干细胞中基因的开启和关闭。我们发现，在旧的骨髓干细胞中，有两组基因似乎更活跃。为了验证这些基因是否真的很重要，我们观察了它们编码的细胞成分的“生产”线。我们发现，如果我们篡改这些生产线，我们就能够逆转骨髓细胞中与年龄相关的一些影响。在这个项目中，我们想更好地了解如何调整这些生产线，以真正逆转骨髓干细胞老化的影响。特别是，我们想了解篡改其中一条生产线(称为TGFbeta信号通路)如何能够增加白细胞的产生，并更好地预防感染。我们也有兴趣了解如何篡改这两条生产途径可以增加红细胞的产生。最终，我们希望通过更好地了解这两条生产线是如何干扰骨髓干细胞的正常工作的，我们可能能够设计出逆转这种情况的方法，并有望帮助受这些情况影响的患者。

项目成果

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.