ARYL HYDROCARBON RECEPTOR AND NF-KAPPAB INTERACTIONS

芳基烃受体和 NF-KAPPAB 相互作用

• 批准号: 6136278
• 负责人: Jennifer J Schlezinger
• 金额: $ 3.75万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-24 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6136278
• 关键词: aromatic hydrocarbon receptor; biological signal transduction; carbopolycyclic compound; genetically modified animals; laboratory mouse; nuclear factor kappa beta

Many studies have demonstrated that aryl hydrocarbon receptor (AhR) agonists, including polynuclear aromatic hydrocarbons (PAH) that are ubiquitously distributed in the environment, adversely affect the immune system. Epidemiological analysis of human populations exposed to AhR agonists revealed multi-faceted immune dysfunction in those individuals. Studies in the Sherr laboratory have shown that PAH rapidly induce apoptosis in murine bone marrow stromal cell-dependent preB cells. The preB cell "death signal" was shown to be produced by the stromal cells by an AhR-dependent mechanism. Initial studies have shown that PAH activate NF-kappaB-DNA binding in bone marrow stromal cells and suggested that NF-kappaB also may participate in the pathway leading to production of the "death signal." Therefore, the specific aims of this study were developed to address the hypothesis that AhR agonists alter the NF-kappaB signaling pathway in bone marrow stromal cells, resulting in adverse biological responses potentially including the production of the preB cell "death signal." We will: 1) determine how NF-kappaB is modulated by a model PAH/AhR agonist in bone marrow stromal cells, 2) define PAH-mediated alterations in the kinase signaling cascade upstream of NF-kappaB, and 3) define requirements for AhR-p65 association and transcriptional activity.

许多研究表明，芳基碳氢化合物受体 (AhR) 激动剂，包括环境中普遍分布的多核芳烃 (PAH)，会对免疫系统产生不利影响。 对暴露于 AhR 激动剂的人群的流行病学分析揭示了这些个体存在多方面的免疫功能障碍。 Sherr 实验室的研究表明，PAH 会迅速诱导小鼠骨髓基质细胞依赖性前 B 细胞凋亡。 前B细胞“死亡信号”被证明是由基质细胞通过AhR依赖性机制产生的。 初步研究表明，PAH 激活骨髓基质细胞中 NF-kappaB-DNA 的结合，并表明 NF-kappaB 也可能参与导致“死亡信号”产生的途径。 因此，本研究的具体目的是为了解决以下假设：AhR 激动剂改变骨髓基质细胞中的 NF-kappaB 信号通路，导致可能包括产生前 B 细胞“死亡信号”在内的不良生物反应。 我们将：1) 确定骨髓基质细胞中的模型 PAH/AhR 激动剂如何调节 NF-kappaB，2) 定义 NF-kappaB 激酶信号级联上游激酶信号级联中 PAH 介导的改变，以及 3) 定义 AhR-p65 关联和转录活性的要求。