Novel ARNT-mediated Regulatory Paradigm of AHR Signaling

新型 ARNT 介导的 AHR 信号调节范式

基本信息

批准号：
10378798
负责人：
Casey W Wright
金额：
$ 7.15万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-05 至 2022-05-31
项目状态：
已结题

项目摘要

SUMMARY/ABSTRACT AHR is a cytoplasmic receptor that has affinity for numerous xenobiotic ligands, which include halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), one of the most potent AHR activators, and AHR signaling mediates the detrimental effects of environmental contaminants on body tissues and organs. Ligand binding induces nuclear translocation of AHR and interaction with the AHR binding partner, aryl hydrocarbon receptor nuclear translocator (ARNT), allowing recognition of specific DNA enhancer sequences. More recently endogenous and natural AHR ligands, such as tryptophan metabolites and dietary compounds, have been identified. These ligands induce AHR-mediated immunomodulatory effects such as controlling normal T cell differentiation and immune tolerance. ARNT is expressed as two isoforms, isoform 1 and 3, which differ in only 15 amino acids present in isoform 1. Despite their sequence similarity, we have found that the ARNT isoforms appear to have opposing functions in AHR signaling. As such, through work funded by my parent R01 (ES025809), we find that ARNT activity is a function of both unique phosphorylation of isoform 1 and the given isoform ratio within a particular cell type, which in turn is important for regulating the magnitude/outcome of the AHR response. Moreover, these data suggest that by modulating the ARNT isoform ratio will allow for fine-tuning of an immune response to control inflammation and resolution. Thus, it is critical that my laboratory maintain consistency in the face of the ongoing pandemic in order to continue these cutting- edge investigative avenues that have potential for clinical translation to treat a wide range of environmentally linked immune disorders. Accordingly, this supplement application is to request a portion of salary lost during the past year of COVID shutdowns and quarantine protocols to help support my senior research scientist until new long-term funding is secured.

摘要/摘要 AHR是一种对许多异种配体有亲和力的细胞质受体，其中包括卤化芳基烃，例如2,3,7,8-四氯迪本佐-P-二恶英（TCDD），这是最有效的 AHR激活剂和AHR信号传导介导了环境污染物对人体的有害影响组织和器官。配体结合诱导AHR的核易位和与AHR结合的相互作用伴侣，芳烃受体核转运剂（ARNT），允许识别特定的DNA增强子序列。最近的内源性和天然AHR配体，例如色氨酸代谢物和饮食化合物已被鉴定。这些配体诱导AHR介导的免疫调节作用，例如控制正常的T细胞分化和免疫耐受性。 ARNT表示为两个同工型，同工型1 3，在同工型1中仅存在15个氨基酸。尽管它们的序列相似性，但我们发现 ARNT同工型在AHR信号传导中似乎具有相反的功能。因此，通过由我的父r01（ES025809），我们发现ARNT活性是同工型的独特磷酸化的函数1 并且在特定细胞类型中给定的同工型比，这反过来对调节 AHR响应的幅度/结果。此外，这些数据表明，通过调节ARNT同工型比率将允许对控制炎症和解决方案的免疫反应进行微调。因此，这很关键我的实验室在面对正在进行的大流行时保持一致性，以继续这些削减边缘调查途径具有临床翻译的潜力来治疗各种环境连接的免疫疾病。因此，该补充申请是要求在过去的一年共同关闭和隔离协议，以帮助支持我的高级研究科学家直到获得了新的长期资金。