MOLECULAR MECHANISMS IN NEOPLASIA

本课题的研究重点是多期肿瘤的分析。 Myc诱导法氏囊B细胞淋巴瘤的变化 致癌基因。一种涉及逆转录病毒基因的中心实验策略 移植入法氏囊干细胞用于重建烧蚀胚胎 法氏囊毛囊。这种方法，连同相关的技术， 进一步了解法氏囊淋巴组织增生症中的作用 细胞凋亡性死亡，细胞周期控制，遗传不稳定性，以及 调节这些过程的基因--包括我们拥有的一种新基因 检测到，CTCF可以调节myc的表达。我们的具体目标 主要内容有：(1)通过测定CTCF的生物学功能来分析其生物学功能。 CTCF过表达和抑制的表型后果 正常成纤维细胞，培养的B细胞系，培养的骨髓和 体内正常和肿瘤性B细胞发育。(2)我们将阻止 正常和癌前病变卵泡中细胞凋亡的研究 NR-13的结构性过表达和/或其他细胞死亡 调控基因。通过这种方式，我们将了解更多关于该角色的信息 在所有正常和肿瘤性法氏囊发育的死亡中。(3)我们 将分析表面免疫球蛋白(Ig)之间的关系 多样化、细胞凋亡性死亡和细胞增殖 正常和肿瘤性法氏囊B细胞。这些研究涉及 生殖系免疫球蛋白原性表达效果的观察 法氏囊干细胞及其正常、癌前病变的表面分子 和肿瘤后代。(4)我们将确定Bic是否可以担任 Myc启动的B细胞产生中的一个协同癌基因 淋巴瘤，并将探索激活BIC的机制 在这些肿瘤中的表达。

The focus of this project is the analysis of multistage neoplastic change in B-cell lymphomas induced in the bursa of Fabricius by myc oncogenes. A central experimental strategy involves retroviral gene transfer into bursal stem cells used to reconstitute ablated embryonic bursal follicles. This approach, together with related techniques, allows further insight into the roles in bursal lymphomagenesis of apoptiotic cell death, cell cycle control, genetic instability, and the genes which regulate these processes-including a novel gene we have detected, CTCF, which can regulate myc expression. Our specific aims are: (1) We will analyze the biological function of CTCF by determining the phenotypic consequences of CTCF overexpression and inhibition in normal fibroblasts, cultured B-cell lines, cultured bone marrow and in normal and neoplastic B-cell development in vivo. (2) We will block apoptotic cell death in normal and preneoplastic bursal follicles by constitutive overexpression of NR-13 and/or other cell death regulatory genes. In this fashion, we will learn more about the role of all death in both normal and neoplastic bursal development. (3) We will analyze the relationship between surface immunoglobulin (Ig) diversification, apoptotic cell death and cellular proliferation, in normal and neoplastic bursal B-cells. These studies involve observation of the effects of constitutive expression of germline Ig surface molecules in bursal stem cells and their normal, preneoplastic and neoplastic progeny. (4) We will determine whether bic can act as a cooperating oncogene in the generation of myc-initiated B-cell lymphoma and will explore the mechanisms underlying activation of bic expression in these tumors.