Regulation of E2A in Normal and Aged B Lymphopoiesis

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DESCRIPTION (provided by applicant): The E2A gene encodes basis helix-loop-helix proteins (E47 and El2) which are crucial to the regulation of B lineage cell development within the bone marrow. E2A affects Ig gene rearrangement, proliferation, survival, and differentiation among B lymphocyte precursors. In murine senescence, B lymphocyte development is diminished and, in particular, pre-B cell numbers are generally decreased. Given the importance of E2A, we hypothesize that, in old age, expression of E2A is dysregulated during B lymphopoiesis. This may contribute to reduced B lymphopoiesis in senescence. In order to test this hypothesis, we propose three interrelated Specific Aims. In Specific Aim 1, we will assess the relative levels of expression of E2A, as both mRNA and protein, at distinct stages of B cell differentiation hi senescence in order to determine where decline hi E2A expression and/or function may occur. Specific Aim 2 asks whether transcriptional or post-transcriptional mechanisms result in reduced E2A expression in senescent B cell precursors. This Specific Aim will establish the molecular mechanisms responsible for E2A dysregulation within B cell precursors with particular emphasis on the ubiquitin-proteasome pathway. Specific Aim 3 will establish whether alterations in extrinsic (microenvironmental) signaling within the bone marrow as well as intrinsic signaling, particularly via the pre-B cell receptor, contribute to dysregulation of E2A expression hi senescent B cell precursors. The function of particular bone marrow accessory cell populations (e.g., stroma) in supporting B cell precursor growth and development in senescence will be assessed. These studies will promote understanding of the normal role of E2A hi B lymphopoiesis and the affects of E2A dysregulation on B lymphopoiesis hi senescence. More broadly, these studies will further our understanding of the immune defects which accompany old age and their cellular and molecular mechanisms.