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。自我续订用于维护 前体细胞池，而成熟最终导致 产生成熟的、终末分化的细胞。在.期间 成熟/终末分化过程，发育 程序被建立并执行。我们研究的目的是 是为了确定造血细胞 控制成熟和末端分化的过程。 我们将通过两种方法来研究这些过程。首先，我们 威尔试图确定和描述以下一般因素 允许细胞经历终末分化。要完成 这个目标，我们将扩展我们目前的观察，这表明 C-myc可能对hTERT的表达有普遍影响。 高度特化细胞中的特定基因。我们将表演 对我们已有的基因进行缺失和突变分析 确定的基因被c-myc表达抑制，以找到顺式- 对这种效果负有责任的行为要素。然后，我们将利用 体外转录分析以确定哪些反式作用 造成这种影响的因素是多方面的。我们将使用信息 从这些研究派生出来的，以确定这一可能的作用 对造血细胞基因表达的影响。其次，我们 将确定允许表达以下内容的特定因素 特定的红系基因，将决定这些因素 控制住了。我们将把这些努力的重点放在影响 人类珠蛋白基因的表达和调控。结果是 这些研究的结果可能有助于我们深入了解 造血分化受调控和引导 新的治疗策略的发展 恶性血液病。此外，这些研究可能 结果是确定了可以增强的特定因素 正常和血红蛋白合成及蛋白的表达 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.