Activation of the Ah receptor and epithelial integrity

项目概要/摘要 人类患慢性疾病的风险越来越大，如肥胖症、特应性皮炎、 和炎症性肠病，这些疾病共同影响着数百万人，因此代表了巨大的经济损失。 负担这些疾病的主要促成因素之一是上皮屏障失调。的Ah 受体（AHR）正在成为维持免疫监视和免疫系统完整性的主要因素。 屏障组织（例如皮肤、肠道）。然而，我们对AHR功能的了解往往是令人困惑的， 时间似乎是矛盾的。这项建议将追求创新的理论，即AHR是一个中央监管机构 宿主屏障的稳态，以及对组织上的寄生菌和病原微生物的局部反应 损伤导致AHR活化和增强的上皮修复和屏障功能。我们建立了一个 创新的多学科合作者团队，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，他们为我们理解人类的生存和发展做出了许多独特和开创性的贡献。 因此，我相信我完全有资格领导这项工作。 Perdew实验室的发现包括完整的亚基组成的表征， AHR复合物，并确定配体AHR与炎症转录因子一起作用， 介导细胞因子/趋化因子/生长因子信号传导。我们建议在这里也检查AHR作为一个潜在的 治疗目标的一些慢性疾病。然而，过度或持续激活AHR 可能导致各种毒性，因此我们计划调和这些对立的概念。人类暴露于 来自饮食的AHR配体的复杂混合物，通过微生物群代谢，内源性代谢， 环境污染。因此，有必要更好地了解这一神秘的活动， 受体，不同类型的配体的影响，以及AHR激活所需的适当水平， 保持健康。项目1将鉴定和表征与AHR/选择性AHR相互作用的蛋白质 调节剂（SAhRM）复合物。项目2建议确定和评估饮食/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 饮食或肠道中微生物合成的AHR将提供关于AHR的稳态作用的见解， 低水平外源性配体（如TCDD）暴露的风险。项目3将检查自然， 外源性和合成的AHR配体来调节肠模型中的屏障功能和免疫信号传导。 项目4将研究天然的、外源的和合成的AHR配体增强屏障功能的能力 在皮肤模型中。这一高度创新的提案将探索和验证AHR功能的模型， 许多不同的观察，并将导致重要的见解AHR在疾病过程中的作用。

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.