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:
- 金额:$ 7.15万
- 依托单位:
- 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
- 来源:
- 关键词:ARNT geneAffinityAmino AcidsAromatic HydrocarbonsBindingCytoplasmic ReceptorsDNADataEnvironmental PollutionFundingGenetic Enhancer ElementImmune System DiseasesImmune ToleranceImmune responseInflammationLaboratoriesLigand BindingLigandsLinkMediatingNuclear TranslocationOrganOutcomeParentsPhosphorylationProtein IsoformsProtocols documentationQuarantineResearchResearch SupportResolutionScientistSecureSignal TransductionT cell differentiationTetrachlorodibenzodioxinTissuesTryptophanWagesWorkXenobioticsaryl hydrocarbon receptor ligandcell typeclinical translationcoronavirus diseasedietaryimmunoregulationnovelpandemic diseasepublic health relevanceresponse
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.
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,我们发现
ARNT亚型似乎在AHR信号传导中具有相反的功能。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。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Aryl hydrocarbon receptor nuclear translocator (ARNT) isoforms control lymphoid cancer cell proliferation through differentially regulating tumor suppressor p53 activity.
- DOI:10.18632/oncotarget.7539
- 发表时间:2016-03-08
- 期刊:
- 影响因子:0
- 作者:Gardella KA;Muro I;Fang G;Sarkar K;Mendez O;Wright CW
- 通讯作者:Wright CW
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Casey W Wright其他文献
Casey W Wright的其他文献
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{{ truncateString('Casey W Wright', 18)}}的其他基金
Novel ARNT-mediated Regulatory Paradigm of AhR signaling
新型 ARNT 介导的 AhR 信号调节范式
- 批准号:
9107149 - 财政年份:2016
- 资助金额:
$ 7.15万 - 项目类别:
Novel ARNT-mediated Regulatory Paradigm of AHR Signaling
新型 ARNT 介导的 AHR 信号调节范式
- 批准号:
9477928 - 财政年份:2016
- 资助金额:
$ 7.15万 - 项目类别:
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