Androgen Receptor in B Cell Development and Functions

性激素与免疫和炎症反应的调节有关。雄性小鼠的去势 导致B淋巴细胞在骨髓和外周血中的扩张。这一效果是由于 通过激活雄激素受体(AR)起作用的男性荷尔蒙和雄激素的减少。烧蚀 小鼠的AR也会导致骨髓和外周血中B细胞的扩张，这表明 AR对B淋巴细胞的生成有负调节作用。这项提议的总体目标是澄清 AR调节B淋巴细胞生成的机制。拟议的研究将检验这一假说。 AR对B前体细胞的增殖和凋亡具有调控作用。因此，从骨髓处消融AR 细胞会增加B细胞的增殖和对凋亡的抵抗力，导致B细胞的扩张， 而B细胞的增加可能会导致自身反应性B细胞的产生增加，从而导致自身免疫。 为了验证这一假设，基质细胞和B细胞特异性AR基因敲除(S-ARKO和B-ARKO)小鼠将 为拟议的研究生成的。不同骨髓B细胞在发育过程中的分布 用流式细胞仪检测细胞增殖和凋亡率。产品的生产 还将检测自身抗体和自身反应性B细胞。G-Arko和B-Arko的结果。 ARKO小鼠将与它们的野生型小鼠进行比较，以确定AR在B细胞中的作用部位 淋巴生成。将从纯化的S-ARKO、B-ARKO和野生型小鼠的B细胞中提取RNA以进行鉴定 AR消融对细胞凋亡/增殖相关基因的影响，使AR的作用机制 将被澄清。S-ARKO、B-ARKO和野生型对诱导自身免疫的易感性 将对疾病进行研究和比较。建议的研究结果将提供有用的资料。 为阐明AR在调节B淋巴细胞生成中的作用及其作用机制 自身免疫，以及更好地了解和治疗自身免疫性疾病。

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.