Investigating the transcriptional regulation of the environmental sensor skin disease

描述工作背景，包括在主管自己的团队中进行的工作和以前的工作。[这些信息将被审稿人用来理解拟议研究的背景]。特应性皮炎（AD）是一种慢性炎症性皮肤病，影响全球超过2亿人，严重影响患者的生活质量。虽然自针对特定免疫失调的生物疗法发展以来，治疗方法有所改善，但并非所有患者都对这些疗法有反应，这突出了对更多治疗靶点的需求。芳烃受体（Aryl Hydrocarbon Receptor， AHR）是一种进化上保守的转录因子和环境传感器，在皮肤等屏障器官中表达，在那里它具有稳态作用，维持皮肤屏障的完整性并减少炎症（1,2）。一旦与配体结合，AHR可以转运到细胞核中，在那里它可以与它的伙伴AHR核转运子（ARNT）结合。然后，AHR/ARNT二聚体可以结合到具有二英反应元件（DRE）的DNA区域，启动AHR靶基因或基因电池的转录：AHR编码AHR抑制因子，以及外源代谢细胞色素P450-1酶CYP1A1， CYP1A2和CYP1B1。AHR信号在三个水平上受到调节，这表明了监测AHR通路的生理重要性：AHR抑制因子（AHRR）可以破坏AHR/ARNT二聚体，阻止进一步的转录诱导，AHR的蛋白酶体降解，最重要的是，通过配体代谢的负反馈机制，细胞色素P450-1 （CYP1）家族的酶[1]，旨在通过清除AHR激活后剩余的配体来防止通路过度激活。AHR最有效的外源性配体是2,3,7,8-四氯二苯并-对二恶英（TCDD），它是二恶英中毒的原因。这些外源性配体是稳定的，抵抗CYP1酶的代谢，导致持续的信号传导，进而导致报道的肝毒性和AHR激活诱导的过度免疫抑制。相反，生理配体被CYP1酶快速代谢，导致瞬时信号传导。它们主要来源于色氨酸代谢物和宿主微生物群，这意味着AHR具有生理功能。这些色氨酸代谢物包括皮肤紫外线辐射产生的6-甲酰基林多洛[3,2-b]咔唑（FICZ），微生物代谢产生的吲哚-3-乙酸和吲哚-3-丙酸，以及宿主酶代谢产生的犬尿氨酸（配体前体）和犬尿酸]。我们实验室的研究表明，炎症性皮肤病牛皮癣中AHR通路的失调(3)，以及AD（未发表的数据）中AHR及其靶基因CYP1A1的表达失调。Tapinarof是一种局部AHR激动剂，已经在一项治疗AD的3期临床试验中进行了测试（临床试验标识号NCT05032859），并已被批准用于治疗牛皮癣(4)。Tapinarof治疗减少炎症介质，增加皮肤屏障功能，促进病变清除。然而，AHR激活是一把双刃剑，因为它既具有有益的生理功能，也具有过度免疫抑制的毒性(1)，这突出了对AHR/CYP1A1轴的进一步研究的必要性。研究该轴的细节具有双重重要性：1)保护轴的过度激活可能导致明显的免疫抑制，2)利用其作为炎症性皮肤病治疗靶点的最大潜力

Describe background to the work including that carried out in the supervisor's own team and previous work. [This information will be used by the reviewers to understand the context of the proposed study]. Atopic Dermatitis (AD) is a chronic inflammatory skin disease affecting over 200 million people worldwide and severely impacting the patient's quality of life. While treatment has improved since the development of biological therapies targeting the specific immune dysregulation, not all patients will respond to these therapies, highlighting the need for more therapeutic targets. The Aryl Hydrocarbon Receptor (AHR) is an evolutionarily conserved transcription factor and environmental sensor, expressed at barrier organs, like skin, where it has a homeostatic role, maintaining skin barrier integrity and reducing inflammation (1, 2). Once bound by its ligand, AHR can translocate into the nucleus where it can bind to its partner AHR Nuclear Translocator (ARNT). The AHR/ARNT dimer can then bind to regions of DNA that possess the Dioxin Response Element (DRE), initiating the transcription of AHR's target genes or gene battery: AHRR encoding for the AHR repressor, and the xenobiotic metabolising Cytochrome P450-1 enzymes CYP1A1, CYP1A2, and CYP1B1 . AHR signalling is regulated at three levels indicating a physiological importance for monitoring the AHR pathway: the AHR repressor (AHRR) can disrupt the AHR/ARNT dimer preventing further transcription induction, proteasomal degradation of AHR , and most importantly, a negative feedback mechanism by ligand metabolism by the Cytochrome P450-1 (CYP1) family of enzymes [1] which are designed to prevent overactivation of the pathway by clearing the remaining ligands following AHR activation. AHR most potent exogenous ligand is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), responsible for dioxin poisoning cases [1]. These exogenous ligands are stable and resistant to metabolism by the CYP1 enzymes, leading to persistent signalling which, in turn, contributes to the reported liver toxicity and excessive immune suppression induced by AHR activation. In contrast, physiological ligands are rapidly metabolised by CYP1 enzymes, leading to transient signalling. They are mostly derived from tryptophan metabolites and the host microbiome , which implies a physiological function for AHR. These tryptophan metabolites include 6-formylindolo[3,2-b]carbazole (FICZ) generated by UV radiation in the skin, Indole-3-Acetic Acid and Indole-3-Propionic Acid generated from microbial metabolism, and Kynurenine (ligand precursor) and Kynurenic Acid via host enzymatic metabolism]. Research by our lab has shown a dysregulation in the AHR pathway in the inflammatory skin disease psoriasis (3), as well as in AD (unpublished data) with regards to expression of AHR and its target gene CYP1A1. Tapinarof, a topical AHR agonist, has been tested in a phase 3 clinical trial for AD (Clinical Trial Identifier NCT05032859), and has been approved to treat psoriasis (4). Tapinarof treatment reduces inflammatory mediators, increases skin barrier function, and promotes clearance of the lesions. However, AHR activation is double-edged, as it is capable of beneficial physiological functions as well as toxicity by excessive immunosuppression (1), highlighting the need for further research into the AHR/CYP1A1 axis. The importance of investigating the finer details of this axis is two-fold: 1) Safeguarding as overactivation of the axis can result in overt immunosuppression, and 2) to harness its maximum potential as a therapeutic target for inflammatory skin diseases