Androgen Receptor in B Cell Development and Functions

B 细胞发育和功能中的雄激素受体

• 批准号: 7996771
• 负责人: CHAWNSHANG CHANG
• 金额: $ 3.93万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7996771
• 关键词: Ablation; Affect; Androgen Receptor; Androgens; Antibodies; Antibody Formation; Apoptosis; Apoptotic; Arthritis; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Cell Development; B-Lymphocytes; Bone Marrow; Cell Lineage; Cell Separation; Cells; Coculture Techniques; Collagen; Development; Disease; Flow Cytometry; Generations; Genes; Genotype; Gonadal Steroid Hormones; Immune; In Vitro; Inflammatory Response; Knock-out; Knockout Mice; Link; Lymphopoiesis; Male Castration; Mus; Pathway interactions; Play; Predisposition; Production; Proliferating; RNA; Regulation; Resistance; Role; Serum; Site; Stromal Cells; Testing; Wild Type Mouse; in vivo; male; pathogen; peripheral blood; precursor cell

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.

性激素与免疫和炎症反应的调节有关。 cas 导致骨髓和外周血中B淋巴细胞的扩张。这种效果是由于 雄性激素的还原，雄激素通过激活雄激素受体（AR）起作用。消融 小鼠AR的AR还导致骨髓和外周血中B细胞的扩张，表明 AR在B淋巴细胞中起负调节作用。该提议的总体目的是阐明 AR调节B淋巴管的机制。拟议的研究将检验假设 AR调节B前体细胞的增殖和凋亡。因此，从bonemarrow中消融AR 细胞会增加B细胞的增殖和对B细胞凋亡的抗凋亡，从而导致B细胞膨胀， 而B细胞增加可能导致自反应性B细胞的产生增加，因此自身免疫性。 为了检验该假设，基质细胞和B细胞特异性AR敲除（S-ARKO和B-ARKO）小鼠将是 为拟议的研究生成。沿发育的各种骨髓B细胞的分布 途径及其增殖和凋亡率将由流式细胞仪确定。生产 还将确定自身抗体和自反应性B细胞。从G-Arko和B-获得的结果 将Arko小鼠与野生型同窝仔进行比较，以确定B中AR作用的位点 淋巴管。 RNA将从S-Arko，B-Arko和野生型小鼠的纯化的B细胞中分离出来，以鉴定 与AR消融影响的凋亡/增殖有关的基因，以便AR作用的机制可以 阐明。最后，s-arko，b-arko和野生型自身免疫的敏感性 疾病将是研究并比较。拟议研究的结果将提供有用的信息 阐明AR的作用及其在调节B淋巴管和的作用机制 自身免疫性以及对自身免疫性疾病的更好理解和治疗。

项目成果

Tumor suppressor PAX6 functions as androgen receptor co-repressor to inhibit prostate cancer growth.

• DOI: 10.1002/pros.21052
• 发表时间: 2010-02-01
• 期刊: PROSTATE
• 影响因子: 2.8
• 作者: Shyr, Chih-Rong;Tsai, Men-Yin;Yeh, Shuyuan;Kang, Hong-Yo;Chang, Yun-Chao;Wong, Pei-Ling;Huang, Chao-Cheng;Huang, Ko-En;Chang, Chawnshang
• 通讯作者: Chang, Chawnshang

The role of androgen and androgen receptor in skin-related disorders.

• DOI: 10.1007/s00403-012-1265-x
• 发表时间: 2012-09
• 期刊: Archives of dermatological research
• 影响因子: 3
• 作者: Lai JJ;Chang P;Lai KP;Chen L;Chang C
• 通讯作者: Chang C

Androgen receptor roles in insulin resistance and obesity in males: the linkage of androgen-deprivation therapy to metabolic syndrome.

• DOI: 10.2337/db13-1505
• 发表时间: 2014-10
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Yu IC;Lin HY;Sparks JD;Yeh S;Chang C
• 通讯作者: Chang C

Metformin inhibits nuclear receptor TR4-mediated hepatic stearoyl-CoA desaturase 1 gene expression with altered insulin sensitivity.

• DOI: 10.2337/db10-0393
• 发表时间: 2011-05
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Kim E;Liu NC;Yu IC;Lin HY;Lee YF;Sparks JD;Chen LM;Chang C
• 通讯作者: Chang C

Neutropenia with impaired host defense against microbial infection in mice lacking androgen receptor.

• DOI: 10.1084/jem.20082521
• 发表时间: 2009-05-11
• 期刊: The Journal of experimental medicine
• 作者: Chuang KH;Altuwaijri S;Li G;Lai JJ;Chu CY;Lai KP;Lin HY;Hsu JW;Keng P;Wu MC;Chang C
• 通讯作者: Chang C