Investigating the transcriptional regulation of the environmental sensor skin disease
研究环境传感器皮肤病的转录调控
基本信息
- 批准号:2749392
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:英国
- 项目类别:Studentship
- 财政年份:2022
- 资助国家:英国
- 起止时间:2022 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
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
描述工作的背景,包括在主管自己的团队中进行的工作和以前的工作。[This审查人员将利用这些信息了解拟议研究的背景]。 特应性皮炎(AD)是一种慢性炎症性皮肤病,影响全球2亿多人,严重影响患者的生活质量。虽然自从靶向特异性免疫失调的生物疗法的发展以来,治疗已经有所改善,但并非所有患者都会对这些疗法产生反应,这突出了对更多治疗靶点的需求。芳烃受体(AHR)是一种进化上保守的转录因子和环境传感器,在屏障器官(如皮肤)中表达,在皮肤中具有稳态作用,维持皮肤屏障完整性并减少炎症(1,2)。一旦被其配体结合,AHR可以易位到细胞核中,在那里它可以结合到其伴侣AHR核易位蛋白(ARNT)。然后,AHR/ARNT二聚体可以结合到具有二恶英反应元件(DRE)的DNA区域,启动AHR靶基因或基因组的转录:编码AHR阻遏物的AHRR,以及异生素代谢细胞色素P450-1酶CYP 1A 1,CYP 1A 2和CYP 1B 1。AHR信号传导在三个水平调节,表明监测AHR途径的生理重要性:AHR阻遏物(AHRR)可以破坏AHR/ARNT二聚体,阻止AHR的进一步转录诱导、蛋白酶体降解,最重要的是,细胞色素P450-1(CYP 1)酶家族通过配体代谢的负反馈机制[1]其被设计为通过在AHR活化后清除剩余的配体来防止途径的过度活化。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),是二恶英中毒的主要原因[1]。这些外源性配体是稳定的,对CYP 1酶的代谢具有抗性,导致持续的信号传导,进而导致报告的肝毒性和AHR激活诱导的过度免疫抑制。相反,生理配体被CYP 1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组,这意味着AHR的生理功能。这些色氨酸代谢物包括通过皮肤中的UV辐射产生的6-甲酰基吲哚并[3,2-B]咔唑(FICZ)、通过微生物代谢产生的吲哚-3-乙酸和吲哚-3-丙酸以及通过宿主酶代谢产生的犬尿氨酸(配体前体)和犬尿烯酸。我们实验室的研究表明,炎症性皮肤病银屑病(3)以及AD(未发表数据)中AHR及其靶基因CYP 1A 1表达的AHR途径失调。Tapinarof是一种局部AHR激动剂,已在AD的3期临床试验中进行了测试(临床试验标识符NCT 05032859),并已被批准用于治疗银屑病(4)。Tapinarof治疗减少炎症介质,增加皮肤屏障功能,并促进病灶清除。然而,AHR激活是双刃剑,因为它能够发挥有益的生理功能以及过度免疫抑制的毒性(1),强调需要进一步研究AHR/CYP 1A 1轴。研究这个轴的细节的重要性是双重的: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
项目成果
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其他文献
吉治仁志 他: "トランスジェニックマウスによるTIMP-1の線維化促進機序"最新医学. 55. 1781-1787 (2000)
Hitoshi Yoshiji 等:“转基因小鼠中 TIMP-1 的促纤维化机制”现代医学 55. 1781-1787 (2000)。
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LiDAR Implementations for Autonomous Vehicle Applications
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2021 - 期刊:
- 影响因子:0
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吉治仁志 他: "イラスト医学&サイエンスシリーズ血管の分子医学"羊土社(渋谷正史編). 125 (2000)
Hitoshi Yoshiji 等人:“血管医学与科学系列分子医学图解”Yodosha(涉谷正志编辑)125(2000)。
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Effect of manidipine hydrochloride,a calcium antagonist,on isoproterenol-induced left ventricular hypertrophy: "Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,K.,Teragaki,M.,Iwao,H.and Yoshikawa,J." Jpn Circ J. 62(1). 47-52 (1998)
钙拮抗剂盐酸马尼地平对异丙肾上腺素引起的左心室肥厚的影响:“Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,
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