Sex hormones are linked to regulation of immune and inflammatory responses. Castration of male mice results in expansion of B lymphocytes in the bone marrow and peripheral blood. This effect is due to reduction of male sex hormone, androgen, which acts through activation of androgen receptor (AR). Ablation of AR in mice also leads to expansion of B cells in the bone marrow and peripheral blood, suggesting that AR plays a negative regulatory role in B lymphopoiesis. The overall objective of this proposal is to elucidate the mechanism through which AR regulates B lymphopoiesis. The proposed studies will test the hypothesis that AR regulates proliferation and apoptosis of B precursor cells. Thus, ablation of AR from bonemarrow cells will increase proliferation and and resistance to apoptosis of B cells leading to B cell expansion, whereas increased B cells might result in increased production of self-reactive B cells hence autoimmunity. To test this hypothesis, stromal cell and B cell specific AR knockout (S-ARKO and B-ARKO) mice will be generated for the proposed studies. The distribution of various bone marrow B cells along the developmental pathway and their proliferating and apoptosis rates will be determined by flow cytometry. The production of autoantibody and self-reactive B cell also will be determined. The results obtained from G-ARKO and B- ARKO mice will be compared with their wild type littermates to determine the sites of AR action in B lymphopoiesis. RNA will be isolated from purified B cells of S-ARKO, B-ARKO, and wild type mice to identify the genes related to apoptosis/proliferation affected by AR ablation so that the mechanism of AR action can be elucidated. Finally, the susceptibility of S-ARKO, B-ARKO, and wild type to induction of autoimmune disease will be studies and compared. The results of the proposed studies will provide useful information toward elucidation of the role of AR and its mechanis of action in regulating B-lymphopoiesis and autoimmunity, and better understanding and treatment of autoimmune diseases.
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