CD73 FUNCTION DURING LYMPHOCYTE DEVELOPMENT

研究计划Ecto-5 '-nucleotidase（5'-NT，CD 73）是一种嘌呤补救酶 在正常和恶性人类淋巴细胞表面表达的酶。 5 '-NT具有信号转导能力，如通过以下能力所证明的： 5 '-NT抗体引起人淋巴细胞增殖。 因为高 5 '-NT表达与急性胰腺炎预后不良有关， 淋巴母细胞白血病，这种分子可能传递信号， 促进这些细胞不受控制的增殖。 5'-NT 在淋巴细胞发育过程中表达似乎受到高度调节， 随着T和B细胞的成熟而增加。 的目标 建议的研究是确定调控表达的重要性， 5 '-NT在淋巴细胞分化中的作用，并将通过 在早期T B细胞中不适当地过表达5 '-NT， 在成熟细胞中表达。 5 '-NT将在未成熟的 通过在转基因小鼠中表达人5 ′-NT的鼠胸腺细胞或B细胞 分别在lck启动子或IgH增强子的控制下。 5'-NT 将通过制造敲除小鼠在成熟T和B细胞中被删除。 的 这种不适当表达对胸腺组织学的影响， 成熟小鼠的脾脏、骨髓和淋巴结， 将检查这些淋巴器官中T和B细胞的表型。 的 胎儿胸腺、脾脏和脾脏中T和B细胞发育的个体发生 肝脏，并检查成熟T和B细胞的功能。 小鼠 将观察淋巴瘤的发展，这将是 如果发生的话。 这项工作不仅将揭示新的 深入了解5 '-NT表达调控的重要性 淋巴细胞分化，但也将允许申请人开发 转基因技术的技能，并有助于她的发展， 独立调查员

Research Plans Ecto-5'-nucleotidase (5'-NT, CD73) is a purine salvage enzyme expressed on the surface of normal and malignant human lymphocytes. 5'-NT has signal transducing capabilities as demonstrated by the ability of 5'-NT antibodies to cause human lymphocyte proliferation. Since high expression of 5'-NT is associated with a poor prognosis in acute lymphoblastic leukemia, it is possible that this molecule transmits signals that promote the uncontrolled proliferation of these cells. 5'-NT expression appears to be highly regulated during lymphocyte development, increasing with maturation of both T and B cells. The goals of the proposed research are to determine the importance of regulated expression of 5'-NT in lymphocyte differentiation and will be examined by inappropriately overexpressing 5'-NT in early T B cells and by ablating expression in mature cells. 5'-NT will be overexpressed in either immature murine thymocytes or B cells by expressing human 5'-NT in transgenic mice under the control of the lck promoter or IgH enhancer, respectively. 5'-NT will be deleted in mature T and B cells by making knockout mice. The effect of such inappropriate expression on the histology of the thymus, spleen, bone marrow and lymph nodes in the mature mouse, and on the phenotype of T and B cells in these lymphoid organs, will be examined. The ontogeny of T and B cell development in the fetal thymus, spleen, and liver, and the function of mature T and B cells will be examined. Mice will be observed for the development of lymphoid tumors, which will be characterized if they occur. The proposed work will not only reveal new insights into the importance of regulated expression of 5'-NT during lymphocyte differentiation, but will also allow the applicant to develop skills in transgenic technology and contribute toward her development as an independent investigator.