The cellular and molecular basis of age-dependent anemia: a single cell-based approach

年龄依赖性贫血的细胞和分子基础：基于单细胞的方法

• 批准号: BB/M024350/1
• 负责人: Claus Nerlov
• 金额: $ 57.24万
• 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=BB%2FM024350%2F1
• 关键词: cellular; molecular; basis; age; dependent

As we age our ability to produce the red blood cells that transport oxygen within the body declines, leading to increasing prevalence of anemia (i.e. low red cell mass) with age. This is accompanied by a higher risk of numerous infirmities associated with old age, including loss of mental capabilities, loss of mobility, as well as increased risk of hospitalization and of death associated with surgical procedures. While in some people the cause of the anemia can be identified as chronic inflammation or kidney dysfunction, about a third have no identifiable cause. In this project we will examine if changes to the hematopoietic stem cells (HSCs), the cells that produce all blood cell types, play a role in age-dependent anemia. We have developed a technique that allows us to measure the red cell production of a single HSC, and found that there are different types of HSCs with vastly different ability to make red blood cells. We now wish to examine if changes to the abundance of the different HSC subtypes can account for the decline in red cell production, and in addition, whether such changes are due to influences from the cells that surround and support the HSCs in the bone marrow.The aim of these studies is to identify mechanisms by which the decline in red cell production can be prevented, or ultimately reverted.

随着年龄的增长，我们产生在体内输送氧气的红细胞的能力会下降，导致贫血（即红细胞质量低）的患病率随着年龄的增长而增加。随之而来的是与老年相关的多种疾病的风险增加，包括精神能力丧失、行动能力丧失，以及与外科手术相关的住院和死亡风险增加。虽然对于某些人来说，贫血的原因可以被确定为慢性炎症或肾功能障碍，但大约三分之一的人没有明确的原因。在这个项目中，我们将检查造血干细胞（HSC）（产生所有血细胞类型的细胞）的变化是否在年龄依赖性贫血中发挥作用。我们开发了一种技术，可以测量单个 HSC 的红细胞生成量，并发现不同类型的 HSC 生成红细胞的能力差异很大。我们现在希望检查不同 HSC 亚型丰度的变化是否可以解释红细胞产量的下降，此外，这种变化是否是由于骨髓中包围和支持 HSC 的细胞的影响所致。这些研究的目的是确定可以预防或最终恢复红细胞产量下降的机制。

项目成果

Single-cell RNA sequencing reveals molecular and functional platelet bias of aged haematopoietic stem cells.

• DOI: 10.1038/ncomms11075
• 发表时间: 2016-03-24
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Grover A;Sanjuan-Pla A;Thongjuea S;Carrelha J;Giustacchini A;Gambardella A;Macaulay I;Mancini E;Luis TC;Mead A;Jacobsen SE;Nerlov C
• 通讯作者: Nerlov C

Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD-induced myeloproliferation.

• DOI: 10.1084/jem.20161418
• 发表时间: 2017-07-03
• 期刊: The Journal of experimental medicine
• 作者: Mead AJ;Neo WH;Barkas N;Matsuoka S;Giustacchini A;Facchini R;Thongjuea S;Jamieson L;Booth CAG;Fordham N;Di Genua C;Atkinson D;Chowdhury O;Repapi E;Gray N;Kharazi S;Clark SA;Bouriez T;Woll P;Suda T;Nerlov C;Jacobsen SEW
• 通讯作者: Jacobsen SEW

Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal.

• DOI: 10.1038/ncb3346
• 发表时间: 2016-06
• 期刊: Nature cell biology
• 影响因子: 21.3
• 作者: Pietras EM;Mirantes-Barbeito C;Fong S;Loeffler D;Kovtonyuk LV;Zhang S;Lakshminarasimhan R;Chin CP;Techner JM;Will B;Nerlov C;Steidl U;Manz MG;Schroeder T;Passegué E
• 通讯作者: Passegué E