红系细胞终末分化的排核机制及分化相关基因的克隆与鉴定

【作者】 杜权；

【导师】 薛社普； 贺福初； 张世馥；

【作者基本信息】 中国协和医科大学 ， 细胞生物学， 1998， 博士

【摘要】 发育生物学自1894年由德国生物学家Wilhelm Roux及其同事奠基以来，在一个多世纪的发展过程中一直是生命科学领域的研究热点之一，其中细胞分化与去分化更是倍受重视。在生物体的发育过程中，细胞按照一定的方向进行分化，产生具有不同功能的终末细胞，当这一过程受到干扰时，细胞分化受阻，甚至恶变成为肿瘤细胞。肿瘤细胞在一定条件下可以再分化，恶性表型逆转。因此，细胞的分化-去分化-再分化是一个动态的过程，对其机理的研究可为肿瘤的发生机理研究和防治提供重要的依据。哺乳类红系细胞的分化具有明显的特征，当红系细胞进入终末分化时，细胞开始表达红系特异的珠蛋白，同时细胞形态出现明显的改变，即核固缩进而出现排核。当红系细胞癌变时，细胞停滞于较幼稚的阶段，形成红白血病细胞，其珠蛋白基因处于关闭状态，在一定条件下，红白血病细胞可以重新分化，表达珠蛋白，并且这一过程可以人为控制。因此红系细胞是研究细胞分化与癌变的良好模型。 直至目前为止，文献报道的红系特异的作用因子主要集中于红系分化的早期阶段。但当红系细胞进入终末分化阶段时，出现细胞分裂停止、珠蛋白基因表达、核固缩和排核等一系列特征性改变，涉及与终末分化相关基因开启和关闭的调控因子则尚无确切报道，鉴定这些因子，对阐明红系细胞终末分化的机制及红系细胞恶变的机理有重要的理论意义和实用价值。近年来，本室对哺乳类红系细胞的终末分化，尤其是排核更多还原

【Abstract】 Developmental biology has been the hot point of biological sciences over a century since it was founded by German biologist Roux and his colleagues in 1894. Among so many active fields of developmental biology, cell differentiation and dedifferentiation has being paid more and more attention. When cells become committed to particular developmental fates, they undergo a series of divisions and differentiations, and finally give rise to terminally differentiatal cells specialized in certain functions. If this program is disturbed by some unexpected factors, differentiations are hindered, and cells even become tumor cells. Under some enviromental conditions, some tumor cells redifferentiate and give rise to normal functional terminal cells. So cell differentiation-dedifferentiation-redifferentiation is a dynamic process, and the investigation of its mechanism can provide us some important dates for tumor and its therapy researches. Terminal differentiation of mammalian erythroblasts is characterized by two main peculiar features, such as the active expression of globin gene, the pyknosis and denucleation to the anucleus rcticulocytes. Erythroblasts could become erythroleukemia cells and lost the above characteristics of differentiation stage when the differentiation process is blocked. And under certain conditions, erythroleukemia cells might regain its differentiation capacity and undergo normal differentiation. So erythroblasts provide a good model for the study of cell differentiation and dedifferentiation.Up to now, the reports on the erythroblast differentiation regulatory factors are mainly focused on the early stage of erythroblast, the early erythroblasts are known to be the last stage of EPO dependant. The factors that may regulate the further processes of differentiation and maturation are not known. A series of characterized changes such as cell division stopping, nuclear pyknosis and denucleation, however, are not certain and need to be elucitated. During recent years, Dr. Xue’s group has made intensive studies on the factors related to the terminal differentiation of mammalian erythoblast, including the process of denucleation . Their early works are mainly focused on the morphological更多还原