Developing cellular models to study hematopoiesis

造血是未分化的细胞增殖和分化形成血液中三种主要细胞类型的过程：红细胞（或红细胞）、白细胞（或白细胞）和血小板。转录因子和其他蛋白质的复杂网络相互作用，不断更新人类的血细胞群：例如，每个人体内有~25x1012个红细胞，而红细胞只能维持120天。利用遗传方法，我们的团队已经确定了许多新的基因和突变或DNA序列多态性，这些基因和突变控制着人类血细胞的产生。为了了解这些基因编码的蛋白质如何相互作用以影响造血，我们提出了一个研究计划，将利用新的基因组编辑技术和相关的细胞模型。特别是，我们将使用CRISPR-Cas9方法来修饰造血前体细胞中的基因，分化这些细胞，并使用基于分子生物学，细胞和显微镜的检测相结合来监测对血细胞表型的影响。我们的实验和结果不仅将揭示控制人类造血的基本过程，而且还将扩展研究复杂人体组织中细胞增殖和分化之间相互作用的框架。

Hematopoiesis is the process by which undifferentiated cells proliferate and differentiate to form the three main cell types of the blood: red blood cells (or erythrocytes), white blood cells (or leukocytes) and platelets. A complex network of transcription factors and other proteins interact to constantly renew the populations of blood cells in humans: for instance, each individual has ~25x1012 red blood cells in his or her body, and red blood cells last only 120 days. Using genetic approaches, our group has identified many new genes and mutations or DNA sequence polymorphisms that control the production of blood cells in humans. To understand how the proteins encoded by these genes interact to influence hematopoiesis, we propose a research program that will take advantage of novel genome editing technologies and relevant cellular models. In particular, we will use CRISPR-Cas9 methodology to modify genes in hematopoietic precursor cells, differentiate these cells, and monitor the effect on blood-cell phenotypes using a combination of molecular biology-, cellular-, and microscopy-based assays. Our experiments and results will not only shed light on the fundamental processes that control human hematopoiesis, but also expand a framework to study the interplay between cell proliferation and differentiation in complex human tissues.