RNA quality control and environmental stress
RNA质量控制和环境压力
基本信息
- 批准号:8479369
- 负责人:
- 金额:$ 43.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-04-01 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:5&apos-exoribonucleaseAdultAnimalsAntibodiesAutoantigensAutoimmune DiseasesAutoimmunityBacteriaBerylliumBindingCell NucleusCell physiologyCellsCellular StressClinicalCodeComplexCongenital Heart DefectsCytoplasmDNA DamageDeinococcus radioduransDiseaseDrug DesignElectron MicroscopyElementsEscherichia coliEubacteriumExanthemaExonucleaseExoribonucleasesExposure toFailureFundingGene Expression ProfileGene MutationGoalsHeat Stress DisordersHomeostasisImmune responseImmunoprecipitationMammalian CellMammalsMessenger RNAMetabolic PathwayMetabolismMothersMusMutateMutationNutritionalOrthologous GeneOxidantsParticipantPathway interactionsPatientsPhysiologicalPolyribonucleotide NucleotidyltransferasePopulationProcessProductionProtein BindingProteinsQuality ControlRNARNA BindingRNA DecayRNA SequencesRNA-Binding ProteinsRelative (related person)Repetitive SequenceRetrotranspositionRetrotransposonRibosomal RNARoleShapesSjogren&aposs SyndromeStarvationStressSun ExposureSunlightSymptomsSystemSystemic Lupus ErythematosusTestingTissuesTranscriptTransfer RNAUltraviolet RaysUntranslated RNAYeastsbasecrosslinkembryonic stem cellin vivoinsightkeratinocytemammalian genomenervous system disordernovelpreventreceptorresearch studyresponsescaffoldskin lesiontRNA Precursorultravioletultraviolet irradiation
项目摘要
DESCRIPTION (provided by applicant): Although the failure to degrade cellular RNAs contributes to neurologic disorders and to autoimmune diseases such as systemic lupus erythematosus (SLE), little is known of the molecules and pathways that degrade most aberrant RNAs in mammalian cells. Most RNA does not code for proteins, and truncated and misfolded rRNAs, tRNAs and other noncoding RNAs can be generated by gene mutations, transcriptional errors, and processing mistakes. RNAs can also be damaged by sunlight exposure and other environmental insults. Also, since 30-50% of mammalian genomes consists of repetitive elements, including active retrotransposons and their many truncated and divergent relatives that remain transcriptionally active, transcripts from these elements must be recognized and degraded. Most studies of RNA decay have been carried out in yeast, where an exonuclease complex known as the exosome is a major contributor to noncoding RNA decay. Additional pathways likely contribute in metazoans, as the accumulation of numerous aberrant noncoding RNAs that occurs when exosome subunits are mutated in yeast has not been observed when the subunits are depleted from animal cells. The objective of this project is to characterize a novel pathway by which aberrant noncoding RNAs are handled in mammalian cells and some bacteria. The focus is on the Ro 60 kD autoantigen, an important target of the immune response in patients suffering from SLE and Sjogren's syndrome and a likely participant in several clinical sequelae. Mice lacking Ro develop an autoimmune disease that resembles SLE in patients, and Ro is important for survival after UV irradiation in mammalian cells and at least one eubacterium. Ro is ring-shaped and binds newly synthesized misfolded RNAs such that their single-stranded 3' ends protrude from the Ro central cavity. In the cytoplasm, Ro binds noncoding RNAs called Y RNAs that regulate the subcellular distribution of Ro. In at least one bacterium, Ro and a Y RNA form a complex with a ring-shaped exonuclease, polynucleotide phosphorylase (PNPase), that functions in rRNA degradation during nutritional stress. Our first aim is to test the hypothesis, based on electron microscopy of the bacterial complex, that single-stranded RNA threads through the Ro ring into the PNPase cavity and that the Y RNA scaffolds the complex. Our second aim is to determine the extent to which Ro modulates expression of aberrant transcripts in mouse cells. We will test the hypothesis, based on cross-linking of Ro to bound RNAs in mouse embryonic stem cells, that Ro functions in the decay of transcripts from repetitive elements. Our third aim is to identify the direct targets of Ro following exposure of mammalian cells and bacteria to UV irradiation. Together, these studies should elucidate a novel mechanism for modulating RNA decay by exonucleases, illuminate the role of a clinically important RNA-binding protein in mammalian RNA metabolism, and could yield insights into the roles of noncoding RNA metabolic pathways in adapting RNA populations during stress, a poorly understood but likely important part of maintaining cellular homeostasis.
描述(由申请人提供):尽管未能降解细胞RNA会导致神经系统疾病和自身免疫性疾病,例如全身性红斑狼疮(SLE)(SLE),但鲜为人知的分子和途径降低了哺乳动物细胞中最古怪的RNAS的分子和途径。大多数RNA不为蛋白质编码,并且可以通过基因突变,转录错误和处理错误来生成截短和错误折叠的RRNA,TRNA和其他非编码RNA。阳光暴露和其他环境侮辱也可能会损害RNA。同样,由于30-50%的哺乳动物基因组由重复元素组成,包括活跃的逆转录座子及其许多保持转录活性的截断和发散的亲属,因此必须识别和降解这些元素的转录本。大多数RNA衰减的研究都是在酵母中进行的,在酵母中,一种称为外泌体的外切核酸酶络合物是非编码RNA衰变的主要因素。由于在从动物细胞中耗尽亚基时,尚未观察到在酵母中突变外泌体亚基时发生的许多异常非编码RNA的积累,因此可能会导致多个途径。该项目的目的是表征一种新的途径,通过该途径在哺乳动物细胞和一些细菌中处理异常非编码的RNA。重点是RO 60 KD自动抗原,这是患有SLE和Sjogren综合征患者的免疫反应的重要靶标,并且可能参加了几种临床后遗症。缺乏RO的小鼠会形成一种与患者相似的自身免疫性疾病,而RO对于哺乳动物细胞和至少一种Eubacterium的紫外线照射后的生存至关重要。 RO是环形的,并结合了新合成的错误折叠的RNA,因此它们的单链3'端从RO中央腔伸出。在细胞质中,RO结合了称为Y RNA的非编码RNA,该RNA调节RO的亚细胞分布。在至少一个细菌中,RO和Y RNA形成一个复合物,具有环形外核酸酶,多核苷酸磷酸化酶(PNPase),在营养应激过程中起作用RRNA降解。我们的第一个目的是基于细菌复合物的电子显微镜检验假设,即单链RNA线通过RO环进入PNPase腔,并将Y RNA支架造成复合物。我们的第二个目的是确定RO调节小鼠细胞异常转录本的表达程度。我们将基于RO与小鼠胚胎干细胞中结合的RNA的交联测试假设,该假设在重复元素的转录本衰减中起作用。我们的第三个目的是确定哺乳动物细胞和细菌暴露于紫外线照射后的RO的直接靶标。总之,这些研究应阐明一种新的机制来调节外核酸酶调节RNA衰变,阐明临床上重要的RNA结合蛋白在哺乳动物RNA代谢中的作用,并可以对非编码RNA代谢途径在适应RNA在适应RNA在适应RNA在适应RNA中的作用的作用,从而在适应RNA中的作用。这是维持细胞稳态的知识较低但可能重要的部分。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Sandra L. Wolin其他文献
Sandra L. Wolin的其他文献
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{{ truncateString('Sandra L. Wolin', 18)}}的其他基金
Recruitment of host noncoding RNAs by HIV-1
HIV-1 招募宿主非编码 RNA
- 批准号:
8846742 - 财政年份:2015
- 资助金额:
$ 43.03万 - 项目类别:
Recruitment of host noncoding RNAs by HIV-1
HIV-1 招募宿主非编码 RNA
- 批准号:
9095216 - 财政年份:2015
- 资助金额:
$ 43.03万 - 项目类别:
Recruitment of host noncoding RNAs by XMRV
通过 XMRV 招募宿主非编码 RNA
- 批准号:
8223158 - 财政年份:2011
- 资助金额:
$ 43.03万 - 项目类别:
Recruitment of host noncoding RNAs by XMRV
通过 XMRV 招募宿主非编码 RNA
- 批准号:
8090165 - 财政年份:2011
- 资助金额:
$ 43.03万 - 项目类别:
Antibodies to Ro ribonucleoproteins as biomarkers in Sjogren's syndrome
Ro 核糖核蛋白抗体作为干燥综合征的生物标志物
- 批准号:
7268121 - 财政年份:2006
- 资助金额:
$ 43.03万 - 项目类别:
Antibodies to Ro ribonucleoproteins as biomarkers in Sjogren's syndrome
Ro 核糖核蛋白抗体作为干燥综合征的生物标志物
- 批准号:
7124973 - 财政年份:2006
- 资助金额:
$ 43.03万 - 项目类别:
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