: Transforming Growth Factor-B (TGF-beta) is a potent inhibitor of the in vitro proliferation differentiation, and survival of many cell types including B lineage cells. In mice made deficient in TGF-beta 1 by gene targeting (TGF-B 1-/-), there is an expansion of B-cells and their plasma cell progeny ii peripheral lymphoid organs, a phenotype consistent with the anti-proliferative effects of the cytokine By contrast, we did not observe an equivalent expansion of B-cell progenitors in the bone marrow, but instead have identified an age-dependent reduction in the progenitor cells of the TGF-beta 1-/- mice. Results of pilot studies on B lineage progenitor cells from normal mice indicate that very low doses of TGF-beta may promote the survival or differentiation of pre-B-cells. These observations have led to the hypothesis that TGF-beta positively influences B lineage cell progenitors at specific points in their development. To test this hypothesis, to explore mechanisms, and to understand the unexpected features of B-cell development that arise in the absence of TGF-B 1 in vivo, the following Specific Aims are proposed.
Aim 1 : To define the phenotype and differentiation potential of TGF-beta 1-/- B cell progenitors. In this aim the requirement for T-cells in the progenitor cell deficiency will also be examined.
Aim 2 : To define the TGF-beta-responsive stages of normal B-cell development.
Aim 3 : Td examine the need for autocrine TGF-beta in B-cell development and differentiation in vivo using chimeric mouse models.
Aim 4 : To create in vivo models in which B lineage cells are selectively unresponsive to TGF-B. These studies address basic mechanisms of B-cell development and its deregulation by cytokine deficiency. The mouse models created for these experiments may become valuable tools for studies of autoimmune diseases and TGF-beta-resistant human malignancies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048098-04
Application #
6735650
Study Section
Immunobiology Study Section (IMB)
Program Officer
Nasseri, M Faraz
Project Start
2001-05-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
4
Fiscal Year
2004
Total Cost
$251,125
Indirect Cost
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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