Activation of the Ah receptor and epithelial integrity

Ah 受体的激活和上皮完整性

• 批准号: 9565593
• 负责人: Gary H. Perdew
• 金额: $ 83.48万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 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/9565593
• 关键词: Affect; Agonist; Aryl Hydrocarbon Receptor; Atopic Dermatitis; Chronic Disease; Complex; Complex Mixtures; Diet; Disease; Dose; Economic Burden; Environmental Pollution; Epithelial; 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; Pathogenicity; Physiological; Play; Population; Process; Proteins; Receptor Activation; Risk; Role; Route; Seminal; Series; Signal Transduction; Skin; Source; Tetrachlorodibenzodioxin; Time; Tissues; Toxic effect; Toxicology; Work; chemokine; cytokine; exposed human population; human disease; immunological status; innovation; insight; microbiota; multidisciplinary; receptor; receptor function; repaired; response; theories; therapeutic target; transcription factor

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.

项目概要/摘要 人类患肥胖症、特应性皮炎等慢性疾病的风险越来越大 和炎症性肠病，它们共同影响数百万人，从而带来巨大的经济损失 负担。这些疾病的主要影响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）。然而，我们对 AHR 功能的了解常常令人困惑并且不知所措。 时代显得矛盾。该提案将追求 AHR 是中央监管机构的创新理论 宿主屏障稳态的影响，以及组织对共生微生物和病原微生物的局部反应 损伤导致 AHR 激活并增强上皮修复和屏障功能。我们已经建立了一个 创新的多学科合作团队，旨在提供全面的 了解配体刺激的生理和毒理学途径、活性模式和靶点 上皮屏障（例如肠粘膜和皮肤）内的 AHR 激活。我一直在研究AHR 自 1984 年以来，为我们理解 AHR 的生理和毒理学功能，因此我相信我完全有资格领导这项工作。 Perdew 实验室的发现包括对亚基组成的完整表征 AHR 复合物，以及配体 AHR 与炎症转录因子协同作用的确定 介导细胞因子/趋化因子/生长因子信号传导。我们在此建议也将 AHR 作为潜在的 多种慢性疾病的治疗靶点。然而，AHR 的过度或持续激活 可能导致多种毒性，因此我们计划协调这些对立的概念。人类暴露于 来自饮食的 AHR 配体的复杂混合物，通过微生物代谢、内源代谢和 环境污染。因此，有必要更好地了解这个神秘的活动 受体、不同类别配体的影响以及 AHR 激活所需的适当水平 保持健康。项目 1 将识别和表征与 AHR/选择性 AHR 相互作用的蛋白质 调节剂 (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。天然存在的 AHR 配体的鉴定 饮食或肠道微生物合成将提供有关 AHR 和 低水平外源配体（例如 TCDD）暴露的风险。项目3将考察自然的能力， 外源性和合成的 AHR 配体可调节肠道模型中的屏障功能和免疫信号传导。 项目 4 将检查天然、外源和合成 AHR 配体增强屏障功能的能力 在皮肤模型中。这项高度创新的提案将探索和验证 AHR 功能模型，该模型将 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。