Cellular Determinants of Ah Receptor Signaling

Ah 受体信号转导的细胞决定因素

基本信息

批准号：
8625298
负责人：
THOMAS R SUTTER
金额：
$ 30.68万
依托单位：
UNIVERSITY OF MEMPHIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8625298
关键词：
Address Affect Alleles Amino Acids Aryl Hydrocarbon Receptor Binding Biochemical Biopsy Calcium Cell Culture Techniques Cell Differentiation process Cells Ceramide glucosyltransferase Chemicals Complex Cytochromes Dermatology Dioxins Down-Regulation EP300 gene Environment Environmental Pollutants Enzymes Epidermal Growth Factor Epidermal Growth Factor Receptor Epidermis Exposure to Future Gene Expression Gene Targeting Genes Genetic Transcription Hair follicle structure Health Policy Homeostasis Homologous Gene Human Hyperplasia In Vitro Integrins Keratin Kinetics Knowledge Lead Ligands Manuscripts Maps Measures Mediating Metabolism Metaplastic Methods Modeling Modification Mus Names Pathway interactions Pharmaceutical Preparations Physiological Processes Process Protein Biosynthesis Proteins Public Health Publishing Receptor Activation Receptor Signaling Repression Risk Role Sebaceous Glands Sebum Signal Pathway Signal Transduction Skin Spermatocytes Squamous Epithelium Stratified Epithelium Stratum corneum Tertiary Protein Structure Testing Tetrachlorodibenzodioxin Time Toxic effect Xenobiotics activating transcription factor aryl hydrocarbon receptor ligand body system body water loss carcinogenicity cytokine design exposed human population extracellular filaggrin improved in vivo keratinization keratinocyte keratinocyte differentiation minimally invasive pregnant prenatal prevent public health relevance pup response skin hyperkeratosis translational study

Address Affect Alleles Amino Acids Aryl Hydrocarbon Receptor Binding Biochemical Biopsy Calcium Cell Culture Techniques Cell Differentiation process Cells Ceramide glucosyltransferase Chemicals Complex Cytochromes Dermatology Dioxins Down-Regulation EP300 gene Environment Environmental Pollutants Enzymes Epidermal Growth Factor Epidermal Growth Factor Receptor Epidermis Exposure to Future Gene Expression Gene Targeting Genes Genetic Transcription Hair follicle structure Health Policy Homeostasis Homologous Gene Human Hyperplasia In Vitro Integrins Keratin Kinetics Knowledge Lead Ligands Manuscripts Maps Measures Mediating Metabolism Metaplastic Methods Modeling Modification Mus Names Pathway interactions Pharmaceutical Preparations Physiological Processes Process Protein Biosynthesis Proteins Public Health Publishing Receptor Activation Receptor Signaling Repression Risk Role Sebaceous Glands Sebum Signal Pathway Signal Transduction Skin Spermatocytes Squamous Epithelium Stratified Epithelium Stratum corneum Tertiary Protein Structure Testing Tetrachlorodibenzodioxin Time Toxic effect Xenobiotics activating transcription factor aryl hydrocarbon receptor ligand body system body water loss carcinogenicity cytokine design exposed human population extracellular filaggrin improved in vivo keratinization keratinocyte keratinocyte differentiation minimally invasive pregnant prenatal prevent public health relevance pup response skin hyperkeratosis translational study

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项目摘要

DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxic effects, including carcinogenicity and teratogenicity, of a large class of environmental pollutants known as 'dioxinlike' compounds, named after the most potent congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Studies in Ahr null allele mice show that the AHR is necessary for most of the toxic effects of TCDD. However, the mechanism(s) of toxicity downstream of AHR activation remain(s) elusive. As dioxin toxicity does not require concordant exposure to xenobiotics, and dioxin is not metabolized to a reactive intermediate, additional physiologic processes must be disrupted by exposure to TCDD. In humans exposed to dioxin, the most often observed and best studied toxic response is chloracne. Chloracne is manifested in the skin as hyperkeratinization of the interfollicular squamous epithelium, hyperproliferation and hyperkeratinization of cells of the hair follicle, as well as a metaplastic response of the ductular sebaceous glands. How AHR-mediated changes in gene expression lead to toxicity is not well understood for any organ system including skin. Recently, dioxin via the AHR, was shown to enhance human keratinocyte differentiation and to elevate the expression of three genes involved in cornification, a late part of the differentiation process. Formation of the outermost layer of the skin, the stratum corneum, is essential to epidermal barrier function and provides protection against the outside environment and loss of water from the body. Of importance, epidermal growth factor (EGF) receptor (EGFR) signaling was shown to block both TCDD-AHR-mediated gene expression and cell differentiation. These results may in part explain how dioxin affects epidermal homeostasis and identify one mechanism by which EGFR signaling can repress AHR-mediated transcription in keratinocytes. We propose to test the hypothesis that in the epidermis, TCDD-activated AHR disrupts the epidermal barrier by increasing the transcription of genes involved in the formation and function of the stratum corneum, and that EGFR signaling acts to repress this effect. In this proposal, Aim 1 determines whether the TCDD-activated AHR transcriptionally regulates a prioritized set of epidermal target genes and whether these genes are regulated by the AHR and EGFR pathways by mechanisms similar to what has been described for CYP1A1, the prototypic AHR-regulated gene. Aim 2 elucidates the mechanism(s) by which EGFR signaling represses AHR ligand-dependent activation. Aim 3 extends our results in vivo, to determine whether TCDD affects the timing of formation and the function of the epidermal barrier. Collectively, these proposed studies will greatly enhance our understanding of the effects of TCDD on the skin, and will generate the knowledge that is necessary to design minimally invasive studies using small skin biopsies and tape stripping methods in translational studies of human populations exposed to dioxin.

描述（由申请人提供）：芳基碳氢化合物受体（AHR）是一种经过配体激活的转录因子，它介导了大量的环境污染物，其中包括大量的环境污染物，称为“二氧化物类似”的化合物，以致癌性和致死性为例，以最强大的同源为2,3,7,7,7,7 tock fordib thefib incocn（dioxine）。 AHR无效等位基因小鼠的研究表明，AHR对于TCDD的大多数毒性作用都是必需的。但是，AHR激活下游的毒性机制仍然难以捉摸。由于二恶英毒性不需要与异种生物的一致性接触，并且二恶英不会代谢为反应性中间体，因此必须通过暴露于TCDD来破坏其他生理过程。在暴露于二恶英的人类中，最经常观察到的最经常研究的有毒反应是氯酸。氯酸体现在皮肤中，是毛囊细胞细胞间鳞状上皮的过度分泌，过度增殖和过度分泌化，以及ductiumul骨肌腺的转化反应。对于包括皮肤在内的任何器官系统，AHR介导的基因表达变化如何导致毒性。最近，通过AHR二恶英被证明可以增强人角质形成细胞的分化，并提升了与enterification相关的三个基因的表达，这是分化过程的后期。皮肤最外层的形成，角膜层对于表皮屏障功能至关重要，并为外部环境提供了保护和体内水的损失。重要性，表皮生长因子（EGF）受体（EGFR）信号传导被证明可以阻止TCDD-AHR介导的基因表达和细胞分化。这些结果可能部分解释了二恶英如何影响表皮稳态，并确定一种机制，通过这些机制，EGFR信号可以抑制角质形成细胞中AHR介导的转录。我们建议检验以下假设：在表皮中，TCDD激活的AHR通过增加参与角质层形成和功能的基因的转录来破坏表皮屏障，而EGFR信号传导起来抑制这种效应。在该提案中，AIM 1确定TCDD激活的AHR转录是否调节了优先的表皮靶基因集，以及这些基因是否通过与CYP1A1相似的机制受到AHR和EGFR途径的调节。 AIM 2阐明了EGFR信号抑制AHR配体依赖性激活的机制。 AIM 3扩展了我们的体内结果，以确定TCDD是否影响形成时间和表皮屏障的功能。总的来说，这些提出的研究将大大增强我们对TCDD对皮肤影响的理解，并将在使用小型皮肤活检和胶带剥离方法设计最小的侵入性研究中产生知识，以在暴露于二恶英的人群的翻译研究中。