Novel ARNT-mediated Regulatory Paradigm of AHR Signaling

摘要/摘要 AHR是一种细胞质受体，与许多异种配体有亲和力，包括 卤代芳香烃，如2，3，7，8-四氯二苯并对二恶英(TCDD)，是最有效的化合物之一 AHR激活物和AHR信号转导环境污染物对机体的有害影响 组织和器官。配体结合诱导AHR的核转位及其与AHR结合的相互作用 伴侣，芳烃受体核转运体(ARNT)，允许识别特定的DNA增强子 序列。最近，内源性和天然的AHR配体，如色氨酸代谢物和饮食 化合物，已被鉴定。这些配体诱导AHR介导的免疫调节效应，如 控制正常T细胞分化和免疫耐受。ARNT表达为两种亚型，亚型1 和3，它们在亚型1中只有15个氨基酸不同。尽管它们的序列相似，但我们发现 Arnt异构体似乎在AHR信号转导中具有相反的功能。因此，通过由 我的亲本R01(ES025809)，我们发现Arnt的活性是异构体1的独特磷酸化的函数 和特定细胞类型内给定的异构体比率，这反过来对于调节 AHR反应的规模/结果。此外，这些数据表明，通过调节Arnt亚型 比例将允许微调免疫反应，以控制炎症和解决。因此，它是至关重要的 我的实验室在面对持续的大流行时保持一致性，以便继续这些削减- 具有临床转化潜力的边缘研究途径，可治疗广泛的环境问题 连锁性免疫紊乱。因此，这项补充申请是要求支付在以下期间损失的部分工资 在过去的一年里，COVID关闭和隔离协议帮助支持我的高级研究科学家，直到 新的长期资金已得到保障。

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.