Activation of the Ah receptor and epithelial integrity

Ah 受体的激活和上皮完整性

基本信息

批准号：
10623257
负责人：
Gary H. Perdew
金额：
$ 76.41万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10623257
关键词：
Affect Agonist Aryl Hydrocarbon Receptor Atopic Dermatitis Chronic Disease Complex Complex Mixtures Confusion Diet Disease Dose Economic Burden Environment Environmental Pollution Epithelium Exposure to Growth Factor Health Homeostasis Human Immune signaling Immunologic Surveillance Inflammatory Inflammatory Bowel Diseases Intention Intestinal Mucosa Intestines Knowledge Laboratories Lead Ligands Maintenance Mediating Metabolism Microbe Modeling Obesity Persons Physiological Play Population Process Proteins Qualifying Receptor Activation Risk Role Route Seminal Series Signal Transduction Skin Source Tetrachlorodibenzodioxin Tissues Toxic effect Toxicology Work chemokine commensal microbes cytokine dietary epithelial repair exposed human population human disease immunological status innovation insight microbiota multidisciplinary pathogenic microbe receptor receptor function response theories therapeutic target transcription factor

项目摘要

Project Summary/Abstract The human population is increasingly at risk of developing chronic diseases, such as obesity, atopic dermatitis and inflammatory bowel disease, which together affects millions of people, thus representing a huge economic burden. One of the major contributing factors to these diseases is epithelial barrier dysregulation. The Ah receptor (AHR) is emerging as a major factor in the maintenance of immune surveillance and integrity of barrier tissues (e.g. skin, intestinal tract). However, our knowledge of AHR function is often confusing and at times appears contradictory. This proposal will pursue the innovative theory that the AHR is a central regulator of host barrier homeostasis, and the localized response to commensal and pathogenic microbes upon tissue damage leads to AHR activation and enhanced epithelial repair and barrier function. We have established an innovative multi-disciplinary team of collaborators with the intention of providing a comprehensive understanding of the physiological and toxicological routes of ligand stimulation, modes of activity and targets of AHR activation within epithelial barriers (e.g. intestinal mucosa and skin). I have been studying the AHR since 1984 and have made a number of unique and seminal contributions to our understanding of the physiologic and toxicologic functions of the AHR, thus I believe I am well qualified to lead this effort. Discoveries from the Perdew laboratory include complete characterization of the subunit composition of the AHR complex, and the determination that the liganded AHR works with inflammatory transcription factors to mediate cytokine/chemokine/growth factor signaling. We propose here to also examine the AHR as a potential therapeutic target for a number of chronic diseases. However, excessive or sustained activation of the AHR can lead to a variety of toxicities, so we plan to reconcile these opposing concepts. Humans are exposed to complex mixtures of AHR ligands from the diet, through microbiota metabolism, endogenous metabolism, and environmental contamination. Thus, there is a need to better understand the activities of this enigmatic receptor, the influence of different classes of ligands, and the appropriate level of AHR activation required to maintain health. Project 1 will identify and characterize proteins that interact with the AHR/selective AHR modulator (SAhRM) complexes. Project 2 proposes to identify and assess the significance of dietary/bacterial AHR ligands that are major sources of AHR activity. The identification of naturally occurring AHR ligands in the diet or synthesized by microbes in the gut will provide insights concerning the homeostatic role of the AHR and the risk of low-level exogenous ligand (e.g. TCDD) exposure. Project 3 will examine the ability of natural, exogenous, and synthetic AHR ligands to modulate barrier function and immune signaling in intestinal models. Project 4 will examine the ability of natural, exogenous, and synthetic AHR ligands to enhance barrier function in skin models. This highly innovative proposal will explore and validate a model for AHR function that unifies many diverse observations and will lead to important insights into the role of the AHR in disease processes.

项目摘要/摘要人口越来越有患慢性疾病的风险，例如肥胖，特应性皮炎和炎症性肠道疾病，共同影响数百万的人，因此代表了巨大的经济负担。这些疾病的主要因素之一是上皮屏障失调。啊受体（AHR）正在成为维持免疫监视和完整性的主要因素屏障组织（例如皮肤，肠道）。但是，我们对AHR功能的了解通常令人困惑，并且时代似乎是矛盾的。该提议将追求创新的理论，即AHR是中央监管者宿主障碍稳态，以及对组织上的共生和致病微生物的局部反应损伤导致AHR激活并增强上皮修复和屏障功能。我们已经建立了创新的多学科合作团队，目的是提供全面的了解配体刺激的生理和毒理学途径，活性模式和靶标上皮屏障（例如肠粘膜和皮肤）内的AHR激活的。我一直在研究AHR 自1984年以来，已经为我们的理解做出了许多独特的和开创性的贡献 AHR的生理和毒理学功能，因此我相信我有资格领导这项工作。来自PERDEW实验室的发现包括完全表征 AHR复合物，以及配体AHR与炎症转录因子一起工作的确定介导细胞因子/趋化因子/生长因子信号传导。我们在这里建议还将AHR视为潜力多种慢性疾病的治疗靶标。但是，AHR过多或持续激活可以导致各种毒性，因此我们计划调和这些相反的概念。人类暴露于饮食中AHR配体的复杂混合物，通过微生物群代谢，内源代谢和环境污染。因此，有必要更好地了解这种神秘的活动受体，不同类别的配体的影响以及所需的适当水平的AHR激活水平保持健康。项目1将识别并表征与AHR/选择性AHR相互作用的蛋白质调制器（SAHRM）复合物。项目2提议识别和评估饮食/细菌的重要性 AHR配体是AHR活性的主要来源。鉴定自然存在的AHR配体肠道中微生物合成的饮食或合成的饮食将提供有关AHR和AHR的稳态作用的见解低水平外源配体（例如TCDD）暴露的风险。项目3将检查自然的能力，外源和合成AHR配体在肠模型中调节屏障功能和免疫信号传导。项目4将检查自然，外源和合成AHR配体增强屏障功能的能力在皮肤模型中。这个高度创新的建议将探索和验证统一的AHR功能的模型许多不同的观察结果将导致对AHR在疾病过程中的作用的重要见解。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity.

DOI：
10.1080/19490976.2020.1788899
发表时间：
2020-11-09
期刊：
Gut microbes
影响因子：
12.2
作者：
Dong F;Hao F;Murray IA;Smith PB;Koo I;Tindall AM;Kris-Etherton PM;Gowda K;Amin SG;Patterson AD;Perdew GH
通讯作者：
Perdew GH

Early Life Short-Term Exposure to Polychlorinated Biphenyl 126 in Mice Leads to Metabolic Dysfunction and Microbiota Changes in Adulthood.

DOI：
10.3390/ijms23158220
发表时间：
2022-07-26
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
通讯作者：

Aryl Hydrocarbon Receptor Activation Coordinates Mouse Small Intestinal Epithelial Cell Programming.

DOI：
10.1016/j.labinv.2022.100012
发表时间：
2023-01
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
0
作者：
Xiaoliang Zhou;Debopriya Chakraborty;I. Murray;Denise M Coslo;Zoe Kehs;Anitha Vijay;Carolyn Ton
通讯作者：
Xiaoliang Zhou;Debopriya Chakraborty;I. Murray;Denise M Coslo;Zoe Kehs;Anitha Vijay;Carolyn Ton

The Ah Receptor from Toxicity to Therapeutics: Report from the 5th AHR Meeting at Penn State University, USA, June 2022.