T cells in thymus develop from hematopoietic stem cells (HSCs) in bone marrow (BM), but the cellular intermediates linking HSCs in BM via blood to early T lineage progenitors in thymus remain poorly defined. The long-term goal of the proposed work is to elucidate the cellular and molecular basis for early T cell development. It has recently been determined that early T lineage progenitors (ETPs) in thymus derive from a BM progenitor population distinct from previously described common lymphoid progenitors (CLPs), and that the pathways leading to T and B cells diverge earlier than had been previously appreciated. Experiments are proposed to further define and characterize the intermediate populations that lead from multipotent progenitors in BM, through a circulating progenitor cell in blood, eventually leading to ETPs and their downstream T lineage progeny within the thymus. While cytokines and Notch signals are known to be critical for early T cell development, the cellular intermediates receiving and integrating these multiple signals are largely uncharacterized. Notch signals are probably received by blood-borne hematopoietic progenitors shortly after thymic colonization, but ETP subsets within which these signals operate to result in T lineage commitment are also not characterized. Our goal is to identify a complete lineage of cells leading from HSCs in bone marrow to T lineage cells in thymus. An understanding of the key cellular intermediates in T lineage development is necessary to understand disorders in this process, and will be of basic and critical use in a wide variety of diagnostic and therapeutic endeavors. Hence understanding the T cell defects in aging, the process of malignant transformation in T lineage cells, and gene therapy to correct defects of T cell development and function all require that the steps of hematopoiesis linking HSCs to T cells be understood.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059621-03
Application #
7013198
Study Section
Immunobiology Study Section (IMB)
Program Officer
Macchiarini, Francesca
Project Start
2004-03-01
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
3
Fiscal Year
2006
Total Cost
$348,245
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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