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

随着年龄的增长，我们产生在体内运输氧气的红细胞的能力下降，导致贫血（即低红细胞质量）的患病率随着年龄的增长而增加。这伴随着与老年相关的许多疾病的风险增加，包括丧失智力、丧失行动能力以及住院和与外科手术相关的死亡风险增加。虽然在一些人中，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可确定的原因。在这个项目中，我们将研究造血干细胞（HSC）的变化，造血干细胞产生所有类型的血细胞，在年龄依赖性贫血中发挥作用。我们开发了一种技术，使我们能够测量单个HSC的红细胞产量，并发现不同类型的HSC具有截然不同的红细胞生成能力。我们现在希望研究不同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。这些研究的目的是确定可以预防或最终逆转红细胞产量下降的机制。

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.