Hematopoietic differentiation involves the interaction of genetic events within the cell and biochemical signals in the microenvironment. T lymphocytes derive from multipotent hematopoietic stem cells which migrate from the fetal liver and bone marrow to the thymus. Within the thymus, T cell ontogeny is marked by the sequential appearance of many lineage specific molecules. While the temporal expression of these molecules has been well studied, the molecular mechanisms responsible for the coordinated activation and expression of the genes for these developmental and tissue specific proteins are largely unknown. The human CD7 molecule is one of the earliest markers of the T cell lineage, appearing on multipotent hematopoietic precursors in the fetal liver and bone marrow prior to their migration to the thymus. CD7 continues to be expressed throughout T cell development and is found on 85% of peripheral T cells. The overall goal of these studies is to understand T cell development through the study of the T cell specific gene, CD7. Since CD7 is one of the earliest T lineage specific genes expressed, the activation of this gene may help convey T cell specificity to hematopoietic stem cells. We propose to identify and characterize the cis-acting elements which are responsible for the tissue specific expression of the CD7 gene using both in vivo and in vitro systems. In addition, we will study the possible extinction of CD7 gene expression by negative regulatory elements located upstream of the gene and explore the consequences of retroviral infection on the regulation of the gene. We believe that understanding the transcriptional regulation of the CD7 gene will yield significant knowledge about mechanisms of tissue specificity and the early molecular events associated with T cell lineage determination. Because of the central role of the T cell in modulating the immune response, an understanding of the relationship between normal and abnormal T cell development is crucial to understanding the pathogenesis and etiology of autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR001887-02
Application #
3079366
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1992-09-15
Project End
1997-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
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Lee, D M; Schanberg, L E; Fleenor, D E et al. (1996) The mouse CD7 gene: identification of a new element common to the human CD7 and mouse Thy-1 promoters. Immunogenetics 44:108-14
Lee, D M; Patel, D D; Pendergast, A M et al. (1996) Functional association of CD7 with phosphatidylinositol 3-kinase: interaction via a YEDM motif. Int Immunol 8:1195-203
Schanberg, L E; Lee, D M; Fleenor, D E et al. (1995) Characterization of human CD7 transgenic mice. J Immunol 155:2407-18