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Investigating the molecular mechanisms in controlling the aryl hydrocarbon receptor protein levels

研究控制芳烃受体蛋白水平的分子机制

基本信息

批准号：
9812177
负责人：
WILLIAM K CHAN
金额：
$ 38.28万
依托单位：
UNIVERSITY OF THE PACIFIC-STOCKTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9812177
关键词：
26S proteasome AHR gene Affect Applications Grants Aromatic Polycyclic Hydrocarbons Aryl Hydrocarbon Receptor Autophagocytosis Breast Cancer Cell Cancerous Cell Differentiation process Cell physiology Cells Cervical Chemicals Client Data Dioxins Disease Down-Regulation ERBB2 gene Environmental Pollutants Event Exposure to Eye Neoplasms Gene Expression Genes Grant Heart Hela Cells Helix-Turn-Helix Motifs Human Immune Immune response Inflammatory Knowledge Lead Ligands Link Liver Lung Lysosomes MCF7 cell MDA-MB-468 MG132 Malignant Neoplasms Mediating Molecular Molecular Chaperones Organ Pancreas Physiological Processes Polychlorinated Biphenyls Proteasome Inhibitor Proteins Publishing Research Personnel Stem Cell Development Stem cells T cell differentiation Tetrachlorodibenzodioxin Xenobiotics aryl hydrocarbon receptor ligand drug metabolism environmental chemical experimental study inhibition of autophagy interest knock-down liver development overexpression protein degradation receptor receptor function response transcription factor triple-negative invasive breast carcinoma tumor growth

项目摘要

Project Summary/Abstract The aryl hydrocarbon receptor (AHR) is a ligand-activated basic-helix-loop-helix-PAS transcription factor. This receptor is responsible for our bodily response to exposure of environmental pollutants such as polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and dioxins. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most studied and best known ligand of AHR. Expression of AHR is up-regulated in human cancers and during T cell differentiation. Malfunction of the events affecting the ahr gene expression would undoubtedly cause problems in cancer, aberrant immune response, stem cell development, and our response to toxic environmental chemicals. However, our knowledge of how the AHR protein levels are maintained without ligand treatment is very limited. Our data suggested a strong likelihood that autophagy is responsible for the AHR protein degradation in human cells. In this grant proposal, we will investigate whether and how autophagy regulates the AHR protein levels in human cells. In brief, we will perform experiments to study the following aims: (1) we will determine whether the autophagy-mediated AHR protein degradation occurs in cancerous and normal human cells (Aim 1); we will determine the autophagy mechanism that is involved in the AHR degradation (Aim 2) and (3) we will investigate how triple-negative human breast cancer cells are more sensitive in the autophagy- mediated AHR protein degradation when compared to non-triple-negative breast cancer cells (Aim 3).

项目总结/摘要芳香烃受体（aryl hydrocarbon receptor，AHR）是一种配体激活的碱性-螺旋-环-螺旋-PAS转录因子。这受体负责我们的身体对环境污染物的反应，如多环芳香烃、多氯联苯和二恶英。2，3，7，8-四氯二苯并对二恶英（TCDD）是是AHR研究最多和最知名的配体之一。AHR在人类癌症中的表达上调和T细胞分化期间。影响AHR基因表达的事件的故障无疑会导致癌症、异常免疫反应、干细胞发育以及我们对有毒物质的反应等问题。环境化学品。然而，我们对AHR蛋白水平如何在没有配体的情况下维持的知识，治疗非常有限。我们的数据表明自噬很可能是AHR的原因。人体细胞中的蛋白质降解。在这项拨款申请中，我们将研究自噬是否以及如何调节人类细胞中的AHR蛋白水平。简而言之，我们将进行实验以研究以下目标： (1)我们将确定自噬介导的AHR蛋白降解是否发生在癌细胞和正常细胞中，人类细胞（目的1）;我们将确定自噬机制，参与AHR降解（目的 2)以及（3）我们将研究三阴性人类乳腺癌细胞如何在自噬中更敏感- 当与非三阴性乳腺癌细胞相比时，AHR介导的AHR蛋白降解（Aim 3）。