RNA editing in islet function and inflammation
RNA editing in islet function and inflammation
批准号:
10660192
负责人:
Yuval Dor
金额:
$56.27万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-05-22 至 2027-04-30
关键词:
AbbreviationsAdenosineAdultAlpha CellAntibodiesAntiviral ResponseArchitectureAutoantibodiesAutoimmunityB-LymphocytesBeta CellBiologyCell SeparationCell physiologyCellsCellular biologyCharacteristicsCodeCollaborationsComputer AnalysisD CellsDangerousnessDeaminationDependenceDetectionDevelopmentDiabetes autoantibodiesDouble-Stranded RNAElementsEnzymesFunctional disorderGene ExpressionGenesGeneticGenetic TranscriptionGenomeGenomicsGoalsHealthHumanHuman GenomeImmuneImmune checkpoint inhibitorImmune responseImpairmentInflammationInflammatoryInflammatory ResponseInosineInsulin-Dependent Diabetes MellitusInterferonsIslet CellKnock-outMalignant NeoplasmsMature B-LymphocyteMediatingModificationMolecularMolecular BiologyMusOrganPancreasPathogenicityPhenotypePreventionProteinsRNARNA EditingRag1 MouseResearchResearch DesignRetroelementsRiskRoleStructureT-Cell DepletionT-LymphocyteTestingTissue-Specific Gene ExpressionViralWorkadaptive immunityadenosine deaminaseanterior chambercell typecytosolic receptordiabetes pathogenesisdsRNA adenosine deaminaseendocrine pancreas developmentepitranscriptomicsexperimental studyeye chambergenome wide association studyhelicasehumoral immunity deficiencyimmune cell infiltratein vivoindexinginsulin dependent diabetes mellitus onsetisletknock-downmelanomamouse modelmultiplexed imagingpostnatalpre-clinicalpreventprogramsprotective alleleresponsesensorsingle-cell RNA sequencingtranscriptome
中文摘要
RNA编辑是一个基本的细胞过程,涉及一些腺苷的脱氨基,
腺苷脱氨酶Adar 1(阿达尔)和Adar 2(ADARB 1)将RNA转化为肌苷。
最近的研究表明,RNA编辑的关键作用是破坏双链RNA,
由插入基因组中的反转录元件产生的双链RNA(dsRNA)结构,
在表达的基因中定位。由这样的序列构型形成的dsRNA是一种双链RNA。
一种古老的抗病毒干扰素反应的强大而危险的激活剂,这可能导致
致病性炎症虽然RNA编辑已经在一些器官中进行了研究,
在癌症中,关于阿达尔酶在胰岛细胞功能中的作用知之甚少,
健康我们的目标是阐明RNA编辑在胰岛中的作用,特别是在α和β细胞中,
β细胞引人注目的是,1型糖尿病(T1D)的GWAS研究揭示了保护性变异
IFIH1/MDA5是一种胞质受体,可识别来自
病毒或内源性来源,并激发炎症反应。因此,缺陷RNA编辑
原则上可有助于自身免疫之前的胰岛抗病毒应答。我们
假设β细胞中受损RNA编辑和内源性dsRNA的积累
触发IFIH 1依赖性干扰素反应,导致胰岛炎症,从而导致β
细胞功能障碍和潜在的自身免疫。在我们的初步调查中,我们发现,
体内成年小鼠β细胞或人类胰岛中A-to-IRNA编辑的破坏引发了一种新的免疫抑制剂,
干扰素应答在Adar 1缺陷β细胞的小鼠中,这会导致大规模免疫
免疫应答定位于胰岛,包括先天免疫细胞和T细胞。阿尔法细胞出现
抵抗β细胞中Adar 1缺陷引起的Adar 1破坏或胰岛炎症。
我们建议:1)在RNA遗传破坏后表征小鼠和人胰岛细胞
编辑,通过敲除或敲低关键RNA编辑酶Adar 1; 2)检查
Adar 1缺乏对β和α细胞功能和活力以及胰岛的影响
炎症和自身免疫;和3)研究分化的分子基础
α和其他胰岛细胞类型对Adart1的依赖性。这项研究是一个结束
3个具有互补专业知识的团队合作:Al Powers(人类胰岛生物学
和功能),Yuval Dor(小鼠模型,分子生物学)和Erez Levanon(计算
RNA编辑分析)。这项工作将揭示RNA编辑的作用,这是一个关键
在胰岛细胞中的表位转录组修饰。它还将反驳或提供临床前支持,
有争议的假设,即有缺陷的RNA编辑可能有助于T1D的各个方面,
发病机制,特别是早期的抗病毒炎症反应。
1
英文摘要
RNA editing, a fundamental cellular process, involves the deamination of some adenosines in
RNA to inosines, by the adenosine deaminases Adar1 (ADAR) and Adar2 (ADARB1).
Recent studies have shown that a critical role of RNA editing is to disrupt double-stranded RNA
(dsRNA) structures that are generated by retroelements inserted in the genome in an inverted
orientation within expressed genes. The dsRNA formed by such sequence configurations is a
powerful and dangerous activator of the ancient antiviral interferon response, which may lead to
pathogenic inflammation. While RNA editing has been studied in the context of some organs
and in cancer, very little is known about the role of ADAR enzymes in islet cell function and
health. Our goal is to elucidate the role of RNA editing in islets, and particularly in alpha and
beta cells. Strikingly, GWAS studies of type 1 diabetes (T1D) have revealed protective variants
of IFIH1/MDA5, a cytosolic receptor that recognizes double-stranded RNA (dsRNA) from either
viral or endogenous origins, and elicits an inflammatory response. Thus, defective RNA editing
can in principle contribute to the islet anti-viral response which precedes autoimmunity. We
hypothesize that impaired RNA editing and accumulation of endogenous dsRNA in beta cells
trigger an IFIH1-dependent interferon response causing islet inflammation, which leads to beta
cell dysfunction and potentially to autoimmunity. In our preliminary findings, we found that
disruption of A-to-I RNA editing in adult mouse beta-cells in vivo or in human islets triggers an
interferon response. In mice with Adar1-deficient beta cells, this leads to massive immune
response localized to islets, including both innate immune cells and T cells. Alpha cells appear
to resist Adar1 disruption or islet inflammation brought about by Adar1 deficiency in beta cells.
We propose to 1) characterize mouse and human islet cells following genetic disruption of RNA
editing, via knockout or knockdown of the key RNA editing enzyme Adar1; 2) examine the
effects of Adar1 deficiency on beta and alpha cell function and viability, as well as islet
inflammation and autoimmunity; and 3) investigate the molecular basis for the differential
dependence of alpha and other islet cell types on Adart1. The proposed research is a close
collaboration between 3 teams with complementary expertise: Al Powers (human islet biology
and function), Yuval Dor (mouse models, molecular biology) and Erez Levanon (computational
analysis of RNA editing). This work will shed light on the role of RNA editing, a key
epitranscriptomic modification, in islet cells. It will also refute or provide pre-clinical support for
the provocative hypothesis that defective RNA editing may contribute to aspects of T1D
pathogenesis, particularly the early, anti-viral inflammatory response.
1
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国内基金
海外基金
基于ADK/Adenosine调控DNA甲基化探讨“利湿化瘀通络”法对2型糖尿病肾病足细胞裂孔膜损伤的干预机制研究
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批准号:82074359
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项目类别:面上项目
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依托单位:
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项目类别:面上项目
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负责人:丁兆平
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依托单位:
Adenosine诱导A1/A2AR稳态失衡启动慢性低灌注白质炎性损伤及其机制
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批准号:81171113
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项目类别:面上项目
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资助金额:55.0万元
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负责人:黄文
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依托单位: