AH RECEPTOR/TRANSCRIPTION FACTOR AS A REGULATOR OF HYDROCARBON BIOACTIVITY

AH 受体/转录因子作为碳氢化合物生物活性的调节剂

• 批准号: 6664575
• 负责人: David H Sherr
• 金额: $ 13.44万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-25 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6664575
• 关键词: T lymphocyte; aromatic hydrocarbon receptor; carbopolycyclic compound; environmental toxicology; gene expression; genetic mapping; genetic promoter element; genetic transcription; genetically modified animals; hazardous substances; human tissue; immunosuppression; laboratory mouse; receptor expression; transcription factor

Polycyclic aromatic hydrocarbons (PAH) and related halogenated hydrocarbons are environmental chemicals present at high concentrations in Superfund hazardous waste sites. These compounds induce cancer, suppress the immune system, and modulate cell growth. At least some, if not all of these responses are mediated by the aryl hydrocarbon receptor (AhR), a cytosolic protein that is converted into a DNA-binding transcription factor following ligand binding. Although primarily known for its regulation of PAH-metabolizing enzymes, the AhR regulates transcription of several genes and appears to affect cell cycle control. AhR activation by environmental chemicals during embryogenesis results in multiple cycle control. AhR activation by environmental chemicals during embryogenesis results in multiple developmental defects. Studies with AhR/null mice suggest that the absence of the AhR also disrupts organ development, indicating that the AhR plays an important role in development even in the absence of exogenous ligands. This conclusion is supported by our demonstration of abnormal T lymphocyte development in AhR transgenic (AhR/TG) mice. Furthermore, AhR up- regulation accompanies antigen-specific human T cell stimulation suggesting a role for the AhR in T cell activation and a mechanism through which AhR ligands may affect antigen-specific immune responsiveness. Given these observations, we have postulated that the AhR plays a role in T cell development and that inappropriate AhR activation by environmental chemicals compromises T cell maturation and function. Three specific aims have been proposed to test this hypothesis and to define factors which control human AhR expression: 1. Define the mechanism responsible for T cell developmental defects in AhR transgenic mice. Using AhR/TG mice produced in our laboratory and AhR/null mice we will determine if the AhR influences deletion of autoreactive clones in the thymus and/or T cell activation and control in secondary lymphoid organs. 2. Determine the role of the AhR in environmental chemical-induced immunosuppression. AhR/TG mice will be used as a highly sensitive system for screening potentially immunotoxic environmental chemicals and as an optimal model for defining the mechanism(s) through which these chemicals mediate immune suppression. 3. Define transcription factors regulating AhR gene expression during activation of primary human peptide specific CD8+ T cells. Having demonstrated AhR up-regulation in human T and B lymphocytes, we will use molecular biology techniques to map regulatory regions in the AhR promoter and to define factors which control AhR transcription. Collectively, results obtained will shed light on the physiological role of the AhR during T cell maturation and on the consequences of AhR ligand exposure during T cell development and activation.

多环芳烃（PAH）和相关的卤代烃是超级基金危险废物处置场中高浓度存在的环境化学物质。这些化合物诱发癌症，抑制免疫系统，并调节细胞生长。这些反应中的至少一些（如果不是全部的话）由芳烃受体（AhR）介导，芳烃受体是在配体结合后转化为DNA结合转录因子的胞质蛋白。虽然主要以其调节PAH代谢酶而闻名，但AhR调节几种基因的转录，并似乎影响细胞周期控制。在胚胎发生过程中，环境化学物质激活AhR导致多周期控制。在胚胎发生过程中，环境化学物质激活AhR导致多种发育缺陷。对AhR/null小鼠的研究表明，AhR的缺乏也会破坏器官发育，这表明AhR即使在缺乏外源性配体的情况下也在发育中起重要作用。这一结论是支持我们的演示异常T淋巴细胞发育AhR转基因（AhR/TG）小鼠。此外，AhR上调伴随抗原特异性人T细胞刺激，表明AhR在T细胞活化中的作用和AhR配体可通过其影响抗原特异性免疫应答的机制。鉴于这些观察结果，我们假设AhR在T细胞发育中起作用，并且环境化学物质对AhR的不适当激活会损害T细胞的成熟和功能。已经提出了三个具体的目标来测试这一假设，并确定控制人类AhR表达的因素：1。定义AhR转基因小鼠中T细胞发育缺陷的机制。使用我们实验室生产的AhR/TG小鼠和AhR/null小鼠，我们将确定AhR是否影响胸腺中自身反应性克隆的缺失和/或次级淋巴器官中T细胞的活化和控制。2.确定AhR在环境化学品诱导的免疫抑制中的作用。AhR/TG小鼠将用作筛选潜在免疫毒性环境化学品的高灵敏度系统，并用作定义这些化学品介导免疫抑制的机制的最佳模型。3.定义在原代人肽特异性CD 8 + T细胞活化过程中调节AhR基因表达的转录因子。在人类T和B淋巴细胞中证实AhR上调后，我们将使用分子生物学技术来绘制AhR启动子中的调控区域，并确定控制AhR转录的因子。总的来说，所获得的结果将揭示在T细胞成熟过程中的AhR的生理作用和AhR配体暴露在T细胞发育和活化过程中的后果。