Estrogenic Regulation of Inflammation Related to TMJD

雌激素对颞下颌关节病相关炎症的调节

• 批准号: 6775614
• 负责人: PHILLIP R KRAMER
• 金额: $ 25.46万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6775614
• 关键词: antibody receptor; antisense nucleic acid; biological signal transduction; clinical research; crosslink; estrogen receptors; estrogens; hormone regulation /control mechanism; human tissue; immunoglobulin G; inflammation; interleukin 1; interleukin 6; macrophage; monocyte; neuroimmunomodulation; phosphorylation; protein quantitation /detection; receptor binding; receptor expression; temporomandibular joint syndrome; tissue /cell culture; transcription factor; transfection /expression vector; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Our long-range goal is to identify and characterize genes through which steroidal hormones affect the onset and/or severity of human disease. The objective of this application is to determine a gene in macrophages affected by estrogen withdrawal, as seen post-partum and at menopause, that functions in immune processes. Our central hypothesis is that changes in estrogen concentrations directly regulate IgG Fc gamma receptor III-A (CD16a) expression resulting in a modulation of pro-inflammatory cytokine production and/or release from macrophages upon receptor binding. This hypothesis is based on our recent findings in vitro that 1) the level of Fc gamma RIIIA transcript increased in macrophage-like THP-1 cells and in primary, peripheral blood macrophages after estrogen removal and 2) that the observed increase was dependent on transcription. The hypothesis also includes data from another lab that binding of Fc gamma RIIIA by anti-Fc gamma RIll monoclonal antibodies stimulates macrophage TNF-alpha and IL-1 alpha release. Fc gamma RIIIA is a receptor that selectively binds IgG molecules, an important rheumatoid factor (RF) in auto-immune disease. Collectively, these data suggest that RF binding of this receptor stimulates cytokine release in rheumatoid arthritis and associated temporomandibular joint disorders (TMJD). To test our central hypothesis aim one will characterize macrophage cytokine production and release from stimulated macrophages after modulating Fc gamma RIIIA expression. TNF-alpha and IL-1 alpha will be measured after changing Fc gamma RIIIA expression levels using various estrogen and Fc gamma RIIIA antisense treatments. Aim two will focus on the mechanism inducing cytokine production and/or release upon Fc gamma RIIIA crosslinking. Signal transduction pathways and activated transcription factors will be identified as well as regulatory TNF-alpha and IL-1 alpha promoter sequences. Aim three will address the mechanism by which estrogen regulates Fc gamma RIIIA gene transcription in macrophages. The function of estrogen receptors ER alpha and/or ER beta will be directly addressed pharmacologically (e.g., antiestrogen) and through mutation studies of the Fc gamma RIIIA promoter.

描述（由申请人提供）：我们的长期目标是识别和表征基因，类固醇激素通过这些基因影响人类疾病的发作和/或严重程度。 本应用的目的是确定巨噬细胞中受雌激素撤退影响的基因（如产后和绝经期所见），该基因在免疫过程中发挥作用。 我们的中心假设是，雌激素浓度的变化直接调节 IgG Fc gamma 受体 III-A (CD16a) 的表达，从而调节促炎细胞因子的产生和/或受体结合时巨噬细胞的释放。 这一假设基于我们最近的体外研究结果：1) 在去除雌激素后，巨噬细胞样 THP-1 细胞和原代外周血巨噬细胞中 Fc gamma RIIIA 转录物水平增加，2) 观察到的增加依赖于转录。 假设 还包括来自另一个实验室的数据，该数据显示抗 Fc γ RIll 与 Fc γ RIIIA 的结合 单克隆抗体刺激巨噬细胞 TNF-α 和 IL-1 α 释放。 Fc gamma RIIIA 是一种选择性结合 IgG 分子的受体，IgG 分子是自身免疫性疾病中重要的类风湿因子 (RF)。 总的来说，这些数据表明该受体的 RF 结合刺激类风湿性关节炎和相关颞下颌关节疾病 (TMJD) 中细胞因子的释放。 为了检验我们的中心假设，目标之一是表征调节 Fc gamma RIIIA 表达后受刺激的巨噬细胞产生和释放的巨噬细胞细胞因子。 在使用各种雌激素和FcγRIIIA反义治疗改变FcγRIIIA表达水平后，将测量TNF-α和IL-1α。 目标二将重点关注 Fc gamma RIIIA 交联时诱导细胞因子产生和/或释放的机制。 将鉴定信号转导途径和激活的转录因子以及调节性 TNF-α 和 IL-1 α 启动子序列。 目标三将解决雌激素调节巨噬细胞中 Fc gamma RIIIA 基因转录的机制。 雌激素受体 ER α 和/或 ER β 的功能将通过药理学（例如抗雌激素）和 Fc γ RIIIA 启动子的突变研究直接解决。