Interleukin 7 (IL-7) has been demonstrated to provide signals via the IL-7 receptor which are required at many stages of lymphocyte development. IL-7 receptor is composed of two different cytokine receptor subunits;the IL-7 receptor alpha chain and the common gamma chain. These two subunits are shared with other cytokine receptors: IL-7 receptor alpha chain is also a subunit of the functional thymic stromal lymphopoiesis receptor, while common gamma chain is a component of functional receptor complexes for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The developmental processes governed by IL-7 receptor signaling include initiation of cell proliferation, protection from apoptotic cell death, and the induction of lineage-specific events, such as gene rearrangement in antigen receptor loci. We have previously shown that cell survival signaling mediated by IL- 7-driven upregulation of an anti-apoptotic protein, Bcl-2, is important for T cell development. On the other hand, IL-7 plays a critical role in regulation of EBF expression at an early phase of B cell development in adult bone marrow. Dysfunction of IL-7 receptor subunits (either IL-7 receptor alpha or common gamma chains) causes profound immunodeficiency in both humans and mice, highlighting the central role IL-7 plays in lymphopoiesis. Although progress has been made in identifying the intracellular mediators of IL-7 receptor signaling that regulate these developmental processes, significant gaps remain.
The specific aims for the next 5 year term are as follows: 1) to determine the role of IL-7 in maintenance of B cell potential in pre-proB/CLP2 cells;2) to determine importance of 414-441 a.a. region of IL-7 receptor alpha in B cell development;and 3) to clarify the role of IL-7R and Flt3 in EBF expression during B cell development. The goal of this project is to elucidate the signaling pathways downstream of IL-7 receptor, which drive specific steps in lymphocyte development, and to determine the genes involved in this process.
Interleukin 7 (IL-7) is an indispensable cytokine for lymphocyte development. However, the signals via the IL-7 receptor necessary for normal lymphocyte development have not been fully understood. The results of this research project will provide us with insights into the regulation of lymphocyte development by an extracellular protein, IL-7, leading to a better understanding of lymphocyte reconstitution following bone marrow transplantation as well as development of leukemia/lymphoma.
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