3'alpha enhancer regulation by AhR and NF-kappaB/Rel proteins

描述（由申请人提供）：化学物质或疾病状态改变免疫基因的调节会严重损害免疫功能。2,3,7,8-四氯二苯并-对二恶英（TCDD或二恶英）是一种可产生多种毒性作用的持久性环境污染物。在这些影响中，免疫功能的改变是在最低暴露水平下最早发现的。关于TCDD对免疫系统的影响的论文比关于任何其他环境危害的论文都要多，但是，尽管经过近30年的研究，TCDD对免疫系统任何方面的作用机制仍然没有明确的认识。此外，TCDD只是可能对人类健康构成重大危害的一大类化学品中的一种代表。TCDD和相关化学物质的许多毒性作用归因于芳烃受体（AhR）的激活以及通过AhR与二恶英响应元件（DRE）的DNA结合而进行的转录调节。虽然TCDD可能通过AhR/DRE机制调节多种免疫基因，但我们之前的研究已经明确证实了TCDD介导的活化B细胞中Ig重链基因表达的抑制，以及TCDD诱导的AhR与位于免疫球蛋白重链3‘调控区（3’ IgH RR）的DRE位点的结合。根据所述的特定目标（SA），我们将验证TCDD通过ahr依赖的3'IgH RR活性调节来抑制Ig重链基因转录和类开关重组的假设，该调节区域涉及蛋白质与DRE和KB基序的结合。SA1：确定在染色质背景下，lps诱导的3'IgH RR活性激活和tcdd诱导的3'IgH RR活性抑制的增强子区域。SA2：确定AhR和/或NF-icB/Rel蛋白是否对TCDD对Ig表达和3'IgH增强子调节的影响至关重要。SA 3：确定TCDD对Ig重链类开关重组的影响。这些研究将有助于我们阐明AhR在调节Ig基因表达中的生理作用的长期目标。这项工作的意义在于，它将为TCDD对b细胞生物学影响的分子基础提供新的见解。这些见解不仅对提高我们对人类暴露于一组持久性环境污染物的风险的理解很重要，而且还可能为调节b细胞功能的方法提供新的视角。

DESCRIPTION (provided by applicant): Altered regulation of immune genes by chemicals or disease states can seriously compromise immune function. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD or dioxin) is a persistent environmental contaminant that produces a variety of toxic effects. Among these effects, alterations in immune function are some of the earliest detected at the lowest exposure levels. There have been more papers written about TCDD's effects on the immune system than about any other environmental hazard, but, despite almost 30 years of research, there is still no clear understanding of TCDD's mechanism of action on any aspect of the immune system. Additionally, TCDD is only one representative of a large class of chemicals that likely constitute a significant hazard to human health. Many of the toxic effects of TCDD and related chemicals have been attributed to activation of the aryl hydrocarbon receptor (AhR) and transcriptional modulation through binding of the AhR to DNA at dioxin responsive elements (DRE). Although there are likely several immune genes modulated by TCDD through an AhR/DRE mechanism, our previous studies have specifically demonstrated TCDD- mediated inhibition of Ig heavy chain gene expression in activated B cells, coupled with TCDD-induced binding of AhR to DRE sites located within the immunoglobulin heavy chain 3' regulatory region (3' IgH RR). With the stated specific aims (SA), we will test the HYPOTHESIS that TCDD inhibits Ig heavy chain gene transcription and class switch recombination through an AhR-dependent modulation of 3'IgH RR activity which involves protein binding to DRE and KB motifs within this regulatory region. SA1: Determine the enhancer regions responsible for LPS-induced activation and TCDD-induced inhibition of 3'IgH RR activity in the context of chromatin. SA2: Determine if AhR and/or NF-icB/Rel proteins are essential to the effects of TCDD on Ig expression and 3'IgH enhancer modulation. SA 3: Determine the effect of TCDD on Ig heavy chain class switch recombination. These studies will contribute to our long-term goal of elucidating the physiological role of the AhR in regulating Ig gene expression. The proposed work is significant in that it will contribute new insights into the molecular basis for the effects of TCDD on B-cell biology. These insights will be important not only to improving our understanding of the human exposure risks to a group of persistent environmental contaminants but they will also likely provide new perspectives on approaches to modulating B-cell function.