Lymphocyte development is a constant hematopoietic renewing process that generates B- and T- lymphocytes, the major cellular components of the immune system. This process is tightly controlled by a complex array of regulatory molecules leading to lymphoid specific gene expression, lineage commitment, and establishment of functional lymphocytes. Alterations in key regulatory genes often result in immune deficiency, autoimmunity, lymphoma, or leukemia. The long term goal of this research is to understand molecular mechanisms underlying lymphocyte development and to provide novel strategies for diagnosis and treatment of lymphoid diseases. Genetic and biochemical studies have established that the bHLH transcription factors encoded by the E2A gene play critical roles in the initiation, differentiation, and function of B-lymphocytes. Altered activity of E2A proteins resulting from translocation at the E2A locus is one of the major causes of childhood lymphocytic leukemias. However, how E2A is involved in B-cell specific gene expression and how E2A itself is regulated is not fully understood. Research proposed here is an ongoing effort to provide answers to these key questions. The specific goal is to understand the function of E2A in the context other signal transduction and gene regulation events leading to B-cell differentiation and immune responses. The investigators plan to use two transgenic mouse lines, they have developed, to investigate the following issues: 1) How is E2A expression regulated in the course of B-cell development and immunity? 2) Does E2A regulate the assembly and expression of immunoglobulin genes? 3) Why is E2A differentially regulated in B and T-cells and what are the consequences of altered E2A expression? Together these studies will provide molecular details of E2A-mediated gene regulation for proper lymphocyte development and function.
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