CONTROL OF THE HEMATOPOIETIC DEVELOPMENTAL PROGRAM

造血细胞来源于有限数量的 具有自我更新特性的前体细胞或干细胞 和成熟。 自我更新提供了维持 前体细胞池，而成熟最终导致 产生成熟的终末分化细胞。 期间 成熟/终末分化过程，发育 程序被建立并执行。 我们学习的目的 是为了确定造血细胞 控制成熟和终末分化的过程。 我们将通过两种方法研究这些过程。 一是 将试图确定和描述一般因素， 使细胞进行终末分化。 完成 为了实现这一目标，我们将扩展我们目前的观察结果， c-myc可能对以下基因的表达有普遍影响： 高度特化细胞中的特定基因。 我们将执行 我们对基因进行了缺失和突变分析， c-myc表达抑制，以找到顺式- 对效果负责的作用元素。 我们将利用在 体外转录分析以确定 这些因素是造成这种效果的原因。 我们将使用信息 从这些研究中得出，以确定这种可能的作用， 对造血细胞中表达的基因的影响。 其次我们 将确定具体的因素，使表达 特定的红细胞基因，并将决定这些因素是如何 控制。 我们将把这些努力集中在影响 人类珠蛋白基因的表达和调控。 结果 这些研究可能会提供深入了解的机制， 造血分化是受调节的， 制定新的战略， 造血系统恶性肿瘤 此外，这些研究可能 导致识别特定的因素，可以增加 正常表达和血红蛋白合成， 血红蛋白病

Hematopoietic cells are derived from a limited number of precursor or stem cells which have the properties of self-renewal and maturation. Self-renewal provides for maintenance of precursor cell pool, while maturation ultimately results in production of mature, terminally differentiated cells. During the maturation/terminal differentiation process, the developmental program is established and executed. The purpose of our studies is to determine the mechanisms by which hematopoietic cells control the processes of maturation and terminal differentiation. We will investigate these processes by two approaches. First, we will attempts to identify and characterize general factors which allow the cell to undergo terminal differentiation. To accomplish this goal, we will extend our current observations which indicate that c-myc may have a general effect on the expression of specific genes in highly specialized cells. We will perform deletional and mutational analysis on genes which we have determined are repressed by c-myc expression to find the cis- acting elements responsible for the effect. We will then utilize in vitro transcriptional analysis to determine which trans acting factors are responsible for the effect. We will use information derived from these studies to determine the possible role of this effect on genes expressed in hematopoietic cells. Secondly, we will identify specific factors which allow the expression of specific erythroid genes and will determine how those factors are controlled. We will focus these efforts on factors which affect the expression and regulation of human globin genes. The results of these studies may provide insight into the mechanisms by which hematopoietic differentiation is regulated and guide the development of new strategies for the treatment of hematopoietic malignancies. Furthermore, these studies may result in the identification of specific factors which can augment the expression of normal and hemoglobin synthesis and hemoglobinopathies.