Post-transcriptional regulation of protein expression by the aryl hydrocarbon receptor

我的研究计划的长期目标是了解芳香烃受体(AhR)的生物学作用，这是一种几乎在所有细胞中都能找到的蛋白质。虽然AhR对环境化学物质有反应，但科学家们并不知道在正常的生物条件下AhR的作用是什么。该项目的目标是在细胞和分子水平上了解AhR如何阻止炎性蛋白的产生。香烟烟雾是一种广泛存在的环境污染物，可增加环氧合酶-2(COX-2)等多种蛋白质的表达。COX-2的长期增加与癌症和关节炎等相关疾病有关。我们实验室最近的研究表明，当称为成纤维细胞的细胞暴露在香烟烟雾中时，AhR可以阻止COX-2蛋白的表达。成纤维细胞是在肺等器官中发现的一种细胞，有助于形成器官结构。我们假设AhR通过一个称为转录后调节的过程控制蛋白质的合成，包括COX-2。这一过程决定了信使核糖核酸产生多少蛋白质，而不是通过转录(DNA到信使核糖核酸)来控制蛋白质的表达。新发现的microRNAs(MiRNAs)是一大类非编码RNA，可以通过导致mRNA的降解来下调蛋白质的表达。目前尚不清楚AhR是否或如何直接控制miRNA以及miRNA调节蛋白质合成的能力。实验室产生的香烟烟雾，以及体外细胞培养模型和细胞、分子、药理和生化技术，将被用来了解AhR在控制蛋白质表达方面的生物学作用。

The long-term goal of my research program is to understand the biological role of the aryl hydrocarbon receptor (AhR), a protein that is found in almost all cells. Although the AhR responds to environmental chemicals, scientists do not know what the role of the AhR is under normal biological conditions. The goal of this project is to understand, at the cellular and molecular levels, how the AhR stop inflammatory proteins from being produced. Cigarette smoke is a wide-spread environmental contaminant that can increase the expression of numerous proteins such as cyclooxygenase-2 (Cox-2). Long-term increases in Cox-2 are associated diseases such as cancer and arthritis. Recent research from our laboratory has shown the AhR stops Cox-2 protein from being expressed when cells called fibroblasts are exposed to cigarette smoke. Fibroblasts are a type of cell found in organs such as the lung that help to give the organ structure. We hypothesize that the AhR controls protein synthesis, including that of Cox-2, by a process called post-transcriptional regulation. This process directs how much protein is generated from mRNA, rather than controlling protein expression by transcription (DNA to mRNA). Newly-discovered microRNAs (miRNAs) are a large group of non-coding RNAs that can down-regulate protein expression by causing degradation of the mRNA. It is not known if or how the AhR directly controls miRNA and the ability of miRNA to regulate protein synthesis. Cigarette smoke generated in the laboratory, together with in vitro cell culture models and cell-, molecular-, pharmacological- and biochemical techniques, will be used to understand the biological role of the AhR in controlling protein expression.