Activation of the Ah receptor and epithelial integrity

项目摘要/摘要 人类人口患慢性疾病的风险越来越大，例如肥胖、特应性皮炎。 和炎症性肠病，这些疾病共同影响着数百万人，因此代表着巨大的经济 负担。这些疾病的主要致病因素之一是上皮屏障失调。《啊》 受体(AHR)是维持免疫监视和免疫完整性的主要因素。 屏障组织(如皮肤、肠道)。然而，我们对AHR功能的了解往往是令人困惑的 时代似乎自相矛盾。这项提案将追求AHR是中央监管者的创新理论 宿主屏障内稳态，以及对组织上共生和致病微生物的局部反应 损伤导致AHR激活，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，意在提供全面的 了解配体刺激的生理和毒理途径、作用方式和靶点 AHR在上皮性屏障(如肠粘膜和皮肤)内的激活。我一直在研究AHR 自1984年以来，他为我们理解 AHR的生理和毒理功能，因此我相信我很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复合体，以及连接的AHR与炎性转录因子共同作用的测定 介导细胞因子/趋化因子/生长因子信号转导。我们建议在这里也将AHR作为一种潜在的 一些慢性病的治疗目标。然而，AHR的过度或持续激活 会导致多种毒性，所以我们计划调和这些对立的概念。人类暴露在 来自饮食的AHR配体的复杂混合物，通过微生物区系代谢、内源性代谢和 环境污染。因此，有必要更好地了解这一谜团的活动 受体，不同类型配体的影响，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 调制器(SAHRM)复合体。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 饮食或由肠道中的微生物合成将提供关于AHR和 暴露于低水平外源配体(如TCDD)的风险。项目3将考察自然的、 外源性和合成的AHR配体在肠道模型中调节屏障功能和免疫信号。 项目4将检验天然、外源和合成的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职能的模型，该模型将统一 许多不同的观察结果，并将导致对AHR在疾病过程中的作用的重要见解。

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.