Age-specific differentiation of multipotent progenitors

项目总结/摘要 该项目的基础是基于对成人和儿童受影响的临床观察 不同的血液疾病，其中许多表现出典型的年龄偏见。越来越多的证据表明 造血系统在发育和衰老过程中正常发生的脚本变化 产生短暂的，年龄特异性的造血基质，这些疾病在其中发展。血液形成 系统经历受控的成熟过程，其中优先化的世系输出、 造血干细胞（HSC）自我更新的速率从早期发育开始变化 通过生物体的成熟。出生后，随着造血系统的老化，这些变化继续 伴有进行性骨髓偏向和HSC自我更新的进一步减少。这些时间上的变化 血液形成的机制似乎受到内在和外在的调节，因为解剖学上的 造血微环境的位置和细胞组成随时间变化， HSC的功能。我们先前的K 08支持的研究已经确定了一种新的表观遗传的潜在机制， 控制从短暂的幼年造血状态向成熟的成年造血的转变。 在这里，我们将研究调节发生在细胞周期中的谱系偏移的分子机制。 造血成熟

PROJECT SUMMARY/ABSTRACT The foundation of this project is based on the clinical observation that adults and children are affected by different blood disorders, many of which show typical age biases. Accumulating evidence supports the notion that the scripted changes that occur normally in the hematopoietic system during development and aging create transient, age-specific hematopoietic substrates in which these diseases develop. The blood forming system undergoes a controlled maturation process wherein the prioritized lineage outputs, mechanisms of lineage restriction, and rates of hematopoietic stem cell (HSC) self-renewal change from early development through maturation of the organism. Postnatally, as the hematopoietic system ages, these changes continue with a progressive myeloid bias and further diminishment of HSC self-renewal. These temporal changes in the mechanisms of blood formation appear to be regulated both intrinsically and extrinsically, as both the anatomic location and cellular composition of the hematopoietic microenvironment change with time in concert with the function of HSCs. Our prior K08-supported research has identified a novel potential mechanism of epigenetic control of the transition from the transient, juvenile state of hematopoiesis to mature adult hematopoiesis. Here, we will investigate molecular mechanisms regulating the shifting lineage biases that occurs during hematopoietic maturation.