RNA splicing regulation during alcohol withdrawal
酒精戒断过程中的 RNA 剪接调节
基本信息
- 批准号:10785159
- 负责人:
- 金额:$ 14.97万
- 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:2023-09-18 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAlcohol consumptionAlcohol withdrawal syndromeAlcoholsAlternative SplicingAntibodiesAnxietyAutomobile DrivingAutopsyAwardBehaviorBehavioralBig DataBindingBinding ProteinsBioinformaticsBrainBrain regionCell physiologyChronicComplementary DNAComplexDarknessDataData ScienceDevelopmentDiagnosisDorsalEnvironmentEthanolEthicsExclusionExonsExtracellular Matrix ProteinsFutureGene DeliveryGene ExpressionGenesGeneticGoalsGrantHeavy DrinkingHigh-Throughput Nucleotide SequencingHippocampusHumanImmune responseImmunoprecipitationIndividualKnowledgeLeadershipLearningLengthLightMediatingMental DepressionMessenger RNAMolecularMorphogenesisNatureNeural ConductionNeuronsOralPhaseProceduresProcessProductionProtein IsoformsProteinsRNARNA BindingRNA SplicingRNA-Binding ProteinsRattusRegulationResearchResearch PersonnelRibonucleoproteinsRoleSignal TransductionSiteSpliceosomesSucroseTechniquesTestingTrainingTranscriptTranslational ResearchUntranslated RNAVariantViralViral VectorWithdrawalWorkWritingalcohol behavioralcohol exposurealcohol use disorderanxiety-like behaviorbehavior testcareer developmentchronic alcohol ingestiondesigndrinking behaviorexperiencegenetic manipulationinnovationinsightknock-downloss of functionmRNA Expressionmalenegative affectneuroadaptationneurogenesisneuroinflammationneurotransmissionnext generation sequencingnoveloverexpressionpreferenceresearch and developmentskillssmall hairpin RNAsuccesstheoriestooltranscriptome sequencing
项目摘要
Project Summary/Abstract
One way in which chronic alcohol exposure produces neuronal adaptations is by changing gene expression.
These changes can influence alcohol-drinking behavior and may lead to the development of alcohol use
disorder (AUD). Additionally, during alcohol withdrawal, gene expression changes can contribute to the
development of negative affective states, such as anxiety and depression, which makes it challenging for
individuals to stop consuming alcohol. Mounting evidence from many species indicates that chronic a lcohol
exposure also leads to alternatively spliced transcripts in different brain regions. Yet the molecular
mechanisms by which alcohol alters RNA splicing remains unknown. This K99/R00 award includes a
comprehensive career development and research plan based on Dr. Luana Carvalho’s preliminary data
showing that withdrawal from chronic alcohol exposure in male rats increases the expression of genes
encoding components of the RNA splicing machinery and leads to changes in RNA splicing. My preliminary
data shows increased expression of the splicing factor Poly r(C) binding protein (PCBP1) in the hippocampus
(HPC) of ethanol withdrawn rats that present with anxiety and depression-like behavior, as well as in the
postmortem HPC of subjects diagnosed with AUD. I also found that PCBP1 is implicated in the mis-splicing
of the Hapln2 gene, an important regulator of neuronal conductivity in which loss of function could negatively
impact neurotransmission in the context of alcohol use. The scientific goal of this K99/R00 is to investigate
RNA splicing, with a focus on PCBP1, as a mechanism by which chronic alcohol exposure and withdrawal
leads to molecular alterations and contributes to the emergence of negative affective states. I will manipulate
PCBP1 expression using viral-mediated gene delivery to test its behavioral relevance during alcohol
withdrawal. I will also perform RNA immunoprecipitation with a PCBP1 antibody, followed by next generation
sequencing to identify PCBP1-targets. Finally, I will perform full-length transcriptome sequencing to identify
the portfolio of alternatively spliced transcripts in the HPC during chronic alcohol exposure and withdrawal.
During my K99 phase, I will gain additional technical training in cutting-edge molecular, bioinformatic and
statistical approaches. I will also enhance my leadership skills and receive considerable training in grant
writing, oral presentations, and ethics that will be crucial to my success as an independent researcher.
During the R00 phase, I will apply all training received to continue this project and further explorer PCBP1
targets in the HPC of humans diagnosed with AUD. Collectively, this work will provide insights into the
molecular mechanisms underlying alcohol withdrawal-induced changes on RNA splicing and negative
affective states, reveal novel targets and testable hypothesis for future functional studies, and facilitate
translational research for finding new targets for AUD treatment.
项目总结/摘要
慢性酒精暴露产生神经适应的一种方式是改变基因表达。
这些变化会影响饮酒行为,并可能导致酒精使用的发展
疾病(AUD)。此外,在戒酒期间,基因表达变化可能会导致
消极情感状态的发展,如焦虑和抑郁,这使得它具有挑战性,
个人停止饮酒。来自许多物种的越来越多的证据表明,慢性酒精
暴露还导致不同脑区域中的选择性剪接转录物。然而,
酒精改变RNA剪接的机制仍然未知。此K99/R 00奖项包括
根据Luana Carvalho博士的初步数据制定的全面职业发展和研究计划
表明雄性大鼠从长期酒精暴露中戒断会增加基因的表达,
RNA剪接机器的编码组分,并导致RNA剪接的变化。我的初步
数据显示海马中剪接因子Poly r(C)结合蛋白(PCBP 1)的表达增加
(HPC)酒精戒断大鼠表现出焦虑和抑郁样行为,
诊断为AUD的受试者的尸检HPC。我还发现PCBP 1参与了
Hapln 2基因是神经传导性的重要调节因子,功能丧失可能会对神经传导性产生负面影响。
在酒精使用的情况下影响神经传递。K99/R 00的科学目标是研究
RNA剪接,重点是PCBP 1,作为慢性酒精暴露和戒断的机制
导致分子改变,并导致负面情感状态的出现。我会操纵
使用病毒介导的基因递送的PCBP 1表达以测试其在酒精期间的行为相关性
戒断我还将用PCBP 1抗体进行RNA免疫沉淀,然后用下一代
测序以鉴定PCBP 1靶。最后,我将进行全长转录组测序,
在慢性酒精暴露和戒断过程中HPC中的选择性剪接转录物组合。
在我的K99阶段,我将获得额外的技术培训,在尖端分子,生物信息学,
统计方法。我也将提高我的领导能力,并在格兰特接受相当多的培训
写作,口头报告,和道德,这将是至关重要的,我作为一个独立的研究人员的成功。
在R 00阶段,我将应用所有收到的培训,继续这个项目,并进一步探索PCBP 1
被诊断患有AUD的人的HPC中的靶点。总的来说,这项工作将提供深入了解
酒精戒断引起的RNA剪接和负性变化的分子机制
情感状态,为未来的功能研究揭示了新的目标和可检验的假设,并促进
转化研究,寻找治疗AUD的新靶点。
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)
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Luana Martins Carvalho其他文献
Luana Martins Carvalho的其他文献
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