Transfer RNAs in Hematopoietic Stem Cell Function
造血干细胞功能中的转移 RNA
基本信息
- 批准号:10735318
- 负责人:
- 金额:$ 31.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAgeAmino AcidsAnemiaAnticodonArginineArginine Specific tRNABiological AssayBloodBlood CellsBone MarrowBone marrow failureBuffersCell CountCell Differentiation processCell MaintenanceCell physiologyCellsChIP-seqCodon NucleotidesDataDefectDevelopmentDiseaseEpitopesEukaryotaFailureFamilyFlow CytometryGene ExpressionGene MutationGenesGeneticGenetic TranscriptionGrantHealthHematological DiseaseHematopoiesisHematopoieticHematopoietic NeoplasmsHematopoietic SystemHematopoietic stem cellsHemorrhageHeterogeneityHousekeeping GeneHumanImmuneImmunityImmunologicsImpairmentIndividualKnock-in MouseLeadLifeMaintenanceMalignant - descriptorMalignant NeoplasmsMessenger RNAMultigene FamilyMusMutationNatural regenerationNatureNeonatalNeuronsNon-MalignantNuclearPancytopeniaPhenotypePopulationProductionProliferatingProtein BiosynthesisProteinsPuromycinRNARNA Polymerase IIIRegulationRibosomal RNARibosomesRoleSignal PathwayStressTestingTissuesTransfer RNATranslationsUntranslated RNAWorkanalogcell typechromatin immunoprecipitationdifferential expressionfetalfetal stem cellfitnesshematopoietic stem cell self-renewalleukemiamRNA Translationmammalian genomemembernovelpolypeptideprogenitorprogramsreconstitutionresponseribosome profilingself-renewalstem cell functionstem cell homeostasisstem cell self renewalstem cellstranscriptometranscriptome sequencingvirtualyoung adult
项目摘要
ABSTRACT
Hematopoietic Stem Cells (HSCs) produce all cells of the blood lineage throughout life. Defects in HSC self-
renewal can lead to immunological defects, anemia, and bone marrow failure. Enhanced HSC self-renewal can
result in hematopoietic malignancies. Thus, precise regulation of HSC self-renewal is essential for maintaining
hematopoietic and human health. Our previous work has shown that adult HSCs tightly control protein synthesis
and that modest changes in protein synthesis impair HSC self-renewal and function. However, the mechanisms
that regulate mRNA translation in HSCs remain largely unknown. Transfer RNAs (tRNAs) are non-coding
adaptor RNAs critical for mRNA translation that are encoded by hundreds of genes in the mammalian genome,
with multiple functional genes capable of decoding virtually every codon. We previously showed that the tRNA
repertoire influences neuronal function but the effect of changes in tRNA expression on hematopoietic cells is
unknown. In preliminary studies, we found that loss of n-Tr22, a member of the five gene arginine UCU tRNA
family significantly impairs HSC maintenance and self-renewal, and this is exacerbated in a sensitized genetic
background lacking the ribosome rescue factor Gtpbp2, resulting in a complete loss of adult, but not fetal HSCs.
We hypothesize that the sensitivity of adult HSCs to the n-Tr22 mutation may be due to differences in the tRNA
repertoire between adult HSCs and restricted progenitors, and between HSCs at different developmental stages.
The impact of tRNA mutations may be further influenced by differential codon usage in the transcriptome of these
cell populations. Finally, there may be cell-type-specific differences in the signaling pathways activated by loss
of a tRNA. We propose to test this hypothesis by using chromatin immunoprecipitation and sequencing to
determine the tRNA repertoire in the hematopoietic system. We will also analyze how this tRNA mutation
influences the maintenance and function of HSCs in the presence and absence of the Gtpbp2 mutation using
flow cytometry and long-term multilineage reconstitution assays. Finally, we will determine the effects of the loss
of n-Tr22 and Gtpbp2 on protein synthesis and gene expression by incorporation of a puromycin analog,
ribosome profiling, and RNA-sequencing. The results from this grant will not only shed light on the role of tRNAs
in regulating mRNA translation in the hematopoietic system, but also provide a means to understand the role of
these genes in the phenotypic heterogeneity common to many human hematopoietic disorders.
摘要
造血干细胞(HSC)在整个生命过程中产生血液谱系的所有细胞。HSC自身缺陷
更新可导致免疫缺陷、贫血和骨髓衰竭。增强型HSC自我更新罐
导致造血系统恶性肿瘤。因此,精确调节HSC自我更新对于维持HSC的存活至关重要。
造血和人类健康。我们以前的工作表明,成年HSC严格控制蛋白质合成
蛋白质合成的适度变化损害HSC的自我更新和功能。然而,机制
调控HSC中mRNA翻译的基因仍然是未知的。转移RNA(tRNA)是非编码的
哺乳动物基因组中数百个基因编码的对mRNA翻译至关重要的衔接RNA,
多个功能基因能够解码几乎每个密码子。我们之前的研究表明,
库影响神经元功能,但tRNA表达的变化对造血细胞的影响,
未知在初步的研究中,我们发现n-Tr 22的缺失,五个基因精氨酸UCU tRNA的成员,
家庭显着损害HSC的维持和自我更新,这是加剧了敏化遗传
背景缺乏核糖体拯救因子Gtpbp 2,导致成体而不是胎儿HSC的完全丧失。
我们推测成年HSC对n-Tr 22突变的敏感性可能是由于tRNA的差异,
成体HSC和限制性祖细胞之间以及不同发育阶段的HSC之间的库。
tRNA突变的影响可能进一步受到这些转录组中不同密码子使用的影响。
细胞群最后,在由损失激活的信号通路中可能存在细胞类型特异性差异
一个tRNA。我们建议通过染色质免疫沉淀和测序来验证这一假设,
确定造血系统中的tRNA库。我们还将分析这种tRNA突变
在存在和不存在Gtpbp 2突变的情况下,
流式细胞术和长期多谱系重建测定。最后,我们将确定损失的影响
n-Tr 22和Gtpbp 2对蛋白合成和基因表达的影响,
核糖体分析和RNA测序。这项资助的结果不仅揭示了tRNAs的作用,
在造血系统中调节mRNA翻译,而且还提供了一种了解
这些基因的表型异质性是许多人类造血系统疾病所共有的。
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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SUSAN L ACKERMAN其他文献
SUSAN L ACKERMAN的其他文献
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{{ truncateString('SUSAN L ACKERMAN', 18)}}的其他基金
The Function of the Cytoplasmic tRNA Repertoire in the Cellular and Molecular Homeostasis of the Mammalian Brain
细胞质 tRNA 库在哺乳动物大脑细胞和分子稳态中的功能
- 批准号:
10550207 - 财政年份:2022
- 资助金额:
$ 31.6万 - 项目类别:
The Function of the Cytoplasmic tRNA Repertoire in the Cellular and Molecular Homeostasis of the Mammalian Brain
细胞质 tRNA 库在哺乳动物大脑细胞和分子稳态中的功能
- 批准号:
10366550 - 财政年份:2022
- 资助金额:
$ 31.6万 - 项目类别:
Ribosome Dysfunction in Neurological Disorders
神经系统疾病中的核糖体功能障碍
- 批准号:
9126621 - 财政年份:2016
- 资助金额:
$ 31.6万 - 项目类别:
Ribosome Dysfunction in Neurological Disorders
神经系统疾病中的核糖体功能障碍
- 批准号:
9271261 - 财政年份:2016
- 资助金额:
$ 31.6万 - 项目类别:
Ribosome Dysfunction in Neurological Disorders
神经系统疾病中的核糖体功能障碍
- 批准号:
9213291 - 财政年份:2016
- 资助金额:
$ 31.6万 - 项目类别:
Ribosome Dysfunction in Neurological Disorders
神经系统疾病中的核糖体功能障碍
- 批准号:
9006366 - 财政年份:2015
- 资助金额:
$ 31.6万 - 项目类别:
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