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.

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National Institute of Allergy and Infectious Diseases (NIAID)
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Cellular and Molecular Immunology - B (CMI)
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Macchiarini, Francesca
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University of Miami School of Medicine
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Frasca, Daniela; Romero, Maria; Diaz, Alain et al. (2012) A molecular mechanism for TNF-?-mediated downregulation of B cell responses. J Immunol 188:279-86
Landin, Ana M; Frasca, Daniela; Harrison, Patrick et al. (2011) E47 retroviral rescue of intrinsic B-cell defects in senescent mice. Aging Cell 10:327-37
Frasca, Daniela; Romero, Maria; Landin, Ana Marie et al. (2010) Protein phosphatase 2A (PP2A) is increased in old murine B cells and mediates p38 MAPK/tristetraprolin dephosphorylation and E47 mRNA instability. Mech Ageing Dev 131:306-14
Alter-Wolf, Sarah; Blomberg, Bonnie B; Riley, Richard L (2009) Deviation of the B cell pathway in senescent mice is associated with reduced surrogate light chain expression and altered immature B cell generation, phenotype, and light chain expression. J Immunol 182:138-47
King, Anne M; Keating, Patricia; Prabhu, Anjali et al. (2009) NK cells in the CD19- B220+ bone marrow fraction are increased in senescence and reduce E2A and surrogate light chain proteins in B cell precursors. Mech Ageing Dev 130:384-92
Alter-Wolf, Sarah; Blomberg, Bonnie B; Riley, Richard L (2009) Old mice retain bone marrow B1 progenitors, but lose B2 precursors, and exhibit altered immature B cell phenotype and light chain usage. Mech Ageing Dev 130:401-8
Frasca, Daniela; Landin, Ana Marie; Riley, Richard L et al. (2008) Mechanisms for decreased function of B cells in aged mice and humans. J Immunol 180:2741-6
Frasca, Daniela; Landin, Ana Marie; Lechner, Suzanne C et al. (2008) Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells. J Immunol 180:5283-90
Frasca, Daniela; Riley, Richard L; Blomberg, Bonnie B (2007) Aging murine B cells have decreased class switch induced by anti-CD40 or BAFF. Exp Gerontol 42:192-203
Frasca, Daniela; Landin, Ana Marie; Alvarez, Juan P et al. (2007) Tristetraprolin, a negative regulator of mRNA stability, is increased in old B cells and is involved in the degradation of E47 mRNA. J Immunol 179:918-27

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