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

AhR 和 NF-kappaB/Rel 蛋白对 3alpha 增强子的调节

• 批准号: 7422450
• 负责人: COURTNEY Elizabeth Williams SULENTIC
• 金额: $ 0.61万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-11 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7422450
• 关键词: AHR gene; Affect; Agonist; Antigens; Aryl Hydrocarbon Receptor; B cell differentiation; B-Lymphocytes; Binding; Burkitt Lymphoma; Celiac Disease; Cell Line; Cells; Chemicals; Chimeric Proteins; Complex; Dioxins; Disease; Electrophoretic Mobility Shift Assay; Elements; Enhancers; Evaluation; Foundations; Gene Expression; Genes; Goals; Human; Human Pathology; Immunity; Immunoglobulin A; Immunoglobulins; Kidney Diseases; Lipopolysaccharides; Luciferases; Measures; Mediating; Mus; NF-kappa B; Nucleic Acid Regulatory Sequences; Numbers; Parents; Pharmacologic Substance; Physiological; Plasmids; Protein Binding; Proteins; Receptor Activation; Regulation; Reporter; Reporter Genes; Repression; Research Personnel; Role; Site; Small Interfering RNA; TNFRSF5 gene; Tandem Repeat Sequences; Technology; Testing; Tetrachlorodibenzodioxin; Toxic effect; Transcriptional Activation; aryl hydrocarbon receptor ligand; chromatin immunoprecipitation; environmental chemical; hazard; human disease; pathogen; programs; receptor expression; research study

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.

描述（由申请人提供）：化学品或疾病状态改变免疫基因的调节可严重损害免疫功能。2，3，7，8-四氯二苯并二恶英（TCDD或二恶英）是一种持久性环境污染物，具有多种毒性作用。在这些影响中，免疫功能的改变是在最低接触水平下最早发现的一些影响。关于TCDD对免疫系统的影响的论文比任何其他环境危害都多，但是，尽管近30年的研究，仍然没有清楚地了解TCDD对免疫系统任何方面的作用机制。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的代表之一。四氯二苯并对二恶英和相关化学品的许多毒性作用都归因于芳香烃受体（AhR）的激活，以及通过AhR与二恶英反应元件（DRE）处的DNA结合而进行的转录调节。虽然可能有几种免疫基因通过AhR/DRE机制被TCDD调节，但我们先前的研究已经明确证明了TCDD介导的对活化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'调节区（3' IgH RR）内的DRE位点的结合。根据上述特定目的（SA），我们将检验以下假设：TCDD通过AhR依赖性调节3 'IgH RR活性（涉及蛋白质与该调节区域内的DRE和KB基序结合）抑制IG重链基因转录和类别转换重组。SA1：确定在染色质中负责LPS诱导的激活和TCDD诱导的3 'IgH RR活性抑制的增强子区域。SA 2：确定AhR和/或NF-κ B/Rel蛋白是否是TCDD对IG表达和3 'IgH增强子调节的作用所必需的。SA 3：确定TCDD对IG重链类别转换重组的影响。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。拟议的工作是重要的，因为它将有助于新的见解TCDD对B细胞生物学的影响的分子基础。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非常重要，而且还可能为调节B细胞功能的方法提供新的视角。