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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA061802-04
Application #
2376900
Study Section
Cancer Institutional Fellowship Review Committee (CT)
Project Start
1994-04-01
Project End
1998-01-01
Budget Start
1997-03-01
Budget End
1998-01-01
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
937727907
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Webb, C F; Dou, S; Buchanan, K L et al. (1997) Reassessment of germline heavy chain transcripts from two murine VH families. Mol Immunol 34:743-50
Resta, R; Thompson, L F (1997) T cell signalling through CD73. Cell Signal 9:131-9
Resta, R; Hooker, S W; Laurent, A B et al. (1997) Insights into thymic purine metabolism and adenosine deaminase deficiency revealed by transgenic mice overexpressing ecto-5'-nucleotidase (CD73). J Clin Invest 99:676-83