Novel ARNT-mediated Regulatory Paradigm of AHR Signaling

总结/摘要 AHR是一种细胞质受体，对许多异生物质配体具有亲和力，包括 卤代芳烃，如2，3，7，8-四氯二苯并-p-二恶英（TCDD）， AHR激活剂和AHR信号传导介导环境污染物对身体的有害影响 组织和器官配体结合诱导AHR核转位及与AHR结合的相互作用 配偶体，芳香烃受体核转运蛋白（ARNT），允许识别特异性DNA增强子 序列的最近，内源性和天然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介导的免疫调节作用， 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，它们的区别仅在于存在于同种型1中的15个氨基酸。尽管它们的序列相似，但我们发现 ARNT亚型在AHR信号传导中似乎具有相反的功能。因此，通过由 我的亲本R 01（ES 025809），我们发现ARNT活性是同种型1的独特磷酸化的功能， 以及特定细胞类型内给定的同种型比例，这反过来对于调节细胞的生长是重要的。 AHR反应的幅度/结果。此外，这些数据表明，通过调节ARNT亚型， 比率将允许微调免疫应答以控制炎症和消退。因此， 我的实验室在面对持续的流行病时保持一致性，以便继续这些切割- 具有临床转化潜力的边缘研究途径，以治疗各种环境问题， 相关的免疫系统疾病因此，这份补充申请是为了要求赔偿 过去一年的COVID关闭和隔离协议，以帮助支持我的高级研究科学家， 新的长期资金已经到位。

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.