The Role of RNA Binding Motif 5 in Traumatic Brain Injury
RNA 结合基序 5 在创伤性脑损伤中的作用
基本信息
- 批准号:10016850
- 负责人:
- 金额:$ 32.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalApoptosisAutophagocytosisAxonBindingBrainCardiovascular DiseasesCaspaseCause of DeathCell DeathCellsCerebral IschemiaCessation of lifeCognitiveDataDiseaseDown-RegulationEnterobacteria phage P1 Cre recombinaseEtiologyEventExonsFoundationsFundingFutureGene DeletionGene ExpressionGenesHippocampus (Brain)HistologicHumanImpairmentIn VitroInjuryKnock-outKnockout MiceKnowledgeLearningLocationMalignant NeoplasmsMeasuresMechanicsMediatingMedicalMemoryMessenger RNAModelingMolecularMonomeric GTP-Binding ProteinsMotorMultiple TraumaMusNervous System TraumaNeurologicNeuronal InjuryNeuronsNormal CellNuclearOrganOutcomePathologicPlayPredispositionProteinsPublishingRBM5 geneRNA BindingRNA SplicingRNA analysisRNA-Binding ProteinsRattusReportingResearchResearch ActivityResource SharingResourcesRoleSignal TransductionSpinal CordSpinal cord injuryStaurosporineStretchingStructureSubfamily lentivirinaeTBI treatmentTestingTimeTissuesToxic effectTraumaTraumatic Brain InjuryUnited States National Institutes of HealthUp-RegulationVertebral columnWorkbehavioral outcomecancer cellcell growthcentral nervous system injuryclinically relevantcognitive functioncontrolled cortical impactdata resourcedisabilitydrug developmentexperimental studygene functionimprovedin vitro testingin vivoin vivo evaluationinnovationknock-downmutantnervous system disorderneurological recoveryneuron lossneuropathologyneuroprotectionneurotoxicneurotoxicitynext generation sequencingnovelnovel therapeutic interventionnovel therapeuticsoverexpressionpreventrepairedsmall moleculetooltranscriptometreatment strategy
项目摘要
ABSTRACT
Traumatic brain injury (TBI) is a leading cause of death and disability in the young. Treatments are
desperately needed to prevent cell death, repair neuronal connectivity, and improve cognitive outcomes after a
TBI. This project will test if gene deletion of RNA binding motif 5 (RBM5) in mice improves molecular and
histological readouts and behavioral outcomes after a controlled cortical impact (CCI) injury.
RNA binding proteins (RBPs) regulate all aspects of mRNA (e.g. RNA splicing, gene expression,
stability, and cellular localization). In recent years a number of RBPs have been associated with the etiology of
disorders ranging from cancer, to cardiovascular and neurological disease. RBM5 is a pro-death RBP. The
mechanisms by which RBM5 induces cell death involves upregulation of pro-death genes and also via the
modulation of mRNA splicing ,which gives rise to toxic proteins with increased potency. Forced overexpression
of RBM5 in cancer cells causes apoptosis, autophagy, and impedes cell growth. Very little is known about the
function(s) of RBM5 in non-cancerous (i.e. normal) cells and tissues. Germane to the CNS, we showed that
RBM5 levels increase after a TBI in mice. Independent of our work, RBM5 levels also reportedly increase after
a traumatic spinal cord injury. It remains to be elucidated if RBM5 activates cell death in primary CNS cells (as
it does in cancer). Our new preliminary data show that RBM5 overexpression in primary rat cortical neurons
increases their susceptibility to a subsequent mechanical stretch-injury. This new finding is in line with our
hypothesis that (1) RBM5 inhibition is a promising new therapeutic strategy for the treatment of CNS injury,
and (2) suggests that RBM5 dysregulation may mediate pathological changes in gene expression which has
been observed to occur after a TBI.
In this project we will definitely test if RBM5 inhibition is neuroprotective in vivo. Novel conditional
RBM5 KO mice will be subjected to a CCI induced injury. Neuropathology in WT versus KOs will be examined
1-21d post-injury. Also, learning and memory function will be examined 14-21d post-injury. Additionally we will
analyze changes in global gene expression/splicing in primary cortical neurons after a mechanical stretch-
injury, and also in which RBM5 levels are manipulated (i.e. by lentivirus mediated knockdown vs.
overexpression). This study represents the most in-depth, largest, and only analysis of RBM5 gene function in
brain which has been done to date.
摘要
创伤性脑损伤(TBI)是年轻人死亡和残疾的主要原因。治疗是
迫切需要防止细胞死亡,修复神经元连接,并改善认知结果后,
创伤性脑损伤该项目将测试小鼠中RNA结合基序5(RBM 5)的基因缺失是否会改善分子和生物学特性。
组织学读数和受控皮质撞击(CCI)损伤后的行为结果。
RNA结合蛋白(RBP)调节mRNA的所有方面(例如RNA剪接,基因表达,
稳定性和细胞定位)。近年来,许多RBP与以下疾病的病因有关:
从癌症到心血管和神经系统疾病。RBM 5是一种亲死亡RBP。的
RBM 5诱导细胞死亡的机制涉及促死亡基因的上调,并且还通过
mRNA剪接的调节,其产生具有增加的效力的毒性蛋白。强迫过表达
RBM 5在癌细胞中的表达导致细胞凋亡、自噬并阻碍细胞生长。关于这一点,我们知之甚少。
RBM 5在非癌(即正常)细胞和组织中的功能。Germane到CNS,我们表明,
小鼠TBI后RBM 5水平增加。独立于我们的工作,据报道,RBM 5水平在
脊髓损伤RBM 5是否激活原代CNS细胞中的细胞死亡(如
在癌症中是这样的)。我们的新的初步数据表明,RBM 5在原代大鼠皮层神经元中的过表达
增加了他们对随后的机械拉伸损伤的易感性。这一新发现与我们的
假设(1)RBM 5抑制是治疗CNS损伤的有前景的新治疗策略,
和(2)表明RBM 5失调可能介导基因表达的病理变化,
在TBI后观察到。
在这个项目中,我们将明确测试RBM 5抑制是否在体内具有神经保护作用。新颖条件
RBM 5 KO小鼠将经受CCI诱导的损伤。将检查WT与科斯的神经病理学
伤后1- 21 d。另外,将在损伤后14- 21天检查学习和记忆功能。此外,我们将
分析机械拉伸后原代皮层神经元中整体基因表达/剪接的变化-
损伤,并且其中RBM 5水平被操纵(即,通过慢病毒介导的敲低vs.
过表达)。这项研究是迄今为止对RBM 5基因功能的最深入、最大和唯一的分析。
迄今为止已经完成的大脑。
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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TRAVIS C JACKSON其他文献
TRAVIS C JACKSON的其他文献
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{{ truncateString('TRAVIS C JACKSON', 18)}}的其他基金
The Role of RNA Binding Motif 5 in Traumatic Brain Injury
RNA 结合基序 5 在创伤性脑损伤中的作用
- 批准号:
10200911 - 财政年份:2018
- 资助金额:
$ 32.7万 - 项目类别:
The Role of RNA Binding Motif 5 in Traumatic Brain Injury
RNA 结合基序 5 在创伤性脑损伤中的作用
- 批准号:
9494899 - 财政年份:2018
- 资助金额:
$ 32.7万 - 项目类别:
The Role of RNA Binding Motif 5 in Traumatic Brain Injury
RNA 结合基序 5 在创伤性脑损伤中的作用
- 批准号:
10445318 - 财政年份:2018
- 资助金额:
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FGF21 Activates RBM3 and is a Novel Drug to Revolutionize Temperature Management
FGF21激活RBM3,是彻底改变温度管理的新药
- 批准号:
9314031 - 财政年份:2017
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The mRNA splicing factor RBM5: A new therapeutic target for TBI
mRNA剪接因子RBM5:TBI的新治疗靶点
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8845278 - 财政年份:2014
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The mRNA splicing factor RBM5: A new therapeutic target for TBI
mRNA剪接因子RBM5:TBI的新治疗靶点
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8749903 - 财政年份:2014
- 资助金额:
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