Androgen Receptor in B Cell Development and Functions

性激素与免疫和炎症反应的调节有关。雄性小鼠去势 导致骨髓和外周血中B淋巴细胞的扩增。这种效应是由于 减少雄性激素，雄激素，其通过激活雄激素受体（AR）起作用。消融 小鼠中AR的增加也导致骨髓和外周血中B细胞的扩增，这表明 AR在B淋巴细胞生成中起负性调节作用。本提案的总体目标是阐明 AR调节B淋巴细胞生成的机制。拟议中的研究将检验这一假设 AR调节B前体细胞的增殖和凋亡。因此，从骨髓中消融AR 细胞将增加增殖和对B细胞凋亡的抗性，导致B细胞扩增， 而增加的B细胞可能导致自身反应性B细胞的产生增加，因此导致自身免疫。 为了检验这一假设，将对基质细胞和B细胞特异性AR敲除（S-ARKO和B-ARKO）小鼠进行免疫接种。 为拟议研究生成。不同类型的骨髓B细胞沿着发育方向的分布 通过流式细胞术测定细胞的增殖和凋亡率。生产 还将测定自身抗体和自身反应性B细胞。从G-ARKO和B- 将ARKO小鼠与其野生型同窝小鼠进行比较，以确定B中AR作用的位点 淋巴细胞生成将从S-ARKO、B-ARKO和野生型小鼠的纯化B细胞中分离RNA，以鉴定 与凋亡/增殖相关的基因受到AR消融的影响，因此AR作用机制可以 被阐明。最后，S-ARKO、B-ARKO和野生型对诱导自身免疫性肿瘤的易感性是一致的。 疾病进行研究和比较。拟议研究的结果将提供有用的信息 旨在阐明AR的作用及其在调节B淋巴细胞生成中的作用机制， 自身免疫，以及更好地理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.