Multimodal Characterization of the Role of Circular RNAs in Alzheimer's Disease
环状 RNA 在阿尔茨海默病中作用的多模式表征
基本信息
- 批准号:10446362
- 负责人:
- 金额:$ 226.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease riskAlzheimer’s disease biomarkerAmyloid beta-ProteinAutopsyBackBehaviorBehavioralBindingBiological AssayBiological ProcessBiomedical ResearchBloodBlood specimenBrainCRISPR/Cas technologyCategoriesCell modelCellsClinicalClinical ResearchClustered Regularly Interspaced Short Palindromic RepeatsCognitionCognitiveComplexDataDementiaDevelopmentDiseaseExonsFunctional disorderGene ExpressionGenesGeneticHippocampus (Brain)Homer 1In VitroIndividualInduced pluripotent stem cell derived neuronsInjectionsIntronsJoining ExonsKnock-outKnockout MiceKnowledgeLinkMAPT geneMediatingMessenger RNAMolecularMusMutationNerve DegenerationNeurologicNeuronsNeurosciencesPathogenicityPathologyPathway AnalysisPathway interactionsPenetrancePhenotypeProtein IsoformsProteinsRNA SplicingResearchRiskRisk FactorsRoleSamplingSenile PlaquesTimeTranscriptTransgenic MiceTranslatingUntranslated RNAUp-RegulationWild Type MouseWorkautosomal dominant Alzheimer&aposs diseasebasebiomarker performancebrain cellbrain tissuecircular RNAcohortdifferential expressionflexibilityfrontal lobegene networkin vivoknock-downknockout animalmRNA Precursormolecular phenotypemouse modelmultimodalitymutation carriernervous system disorderneuropathologynon-dementednovelnovel strategiesoverexpressionpredictive modelingpresenilin-1presenilin-2synaptic functiontau aggregationtooltraffickingtraittranscriptometranscriptome sequencingtranscriptomicsvector
项目摘要
Abstract
Transcriptomic studies in clinical and biomedical research have mainly focused on changes in linear transcripts
to provide knowledge of the genes and co-expression networks implicated in the disease. However, very little is
known about the role of circular RNAs (circRNAs) in Alzheimer's disease (AD). CircRNAs are a novel category
of non-coding RNAs derived from the back-splicing and covalent joining of pre-mRNA exons and introns. We
recently performed a transcriptome-wide analysis of circRNA differential expression in the brain cortex from more
than 621 brain samples from two independent and large cohorts of late-onset sporadic AD cases and
neuropathology-free individuals. We identified specific circRNAs, including circHOMER1, associated with AD
risk and neuropathological traits. This project will use brain tissue to identify additional brain circRNAs implicated
in AD from a cohort that is four-fold larger than the cohort in our previous study. We also plan to investigate
differentially expressed blood circRNAs in AD cases compared with controls to determine their biomarker utility
for creating new prediction models. We will establish a framework for in vitro and in vivo functional
characterization of the role of circRNAs in AD. As proof of principle, we will start by defining the role of
circHOMER1 in AD-related gene expression and related cellular phenotypes. We have found that circHOMER1
is highly expressed in induced pluripotent stem cell (iPSC)-derived neurons. We will use CRISPR/Cas9 to knock
down circHOMER1 as well as use circHOMER1 overexpression (OE) in iPSC-derived neurons from isogenic
controls and AD patient-derived neuronal cultures from pathogenic mutation carriers of APP, PSEN1, PSEN2,
and MAPT genes. To determine whether circHomer1 accelerate/increase AD-related pathology in vivo, we will
generate circHomer1-knockout transgenic mice and cross them with 5XFAD and MAPT-P301S mice. We will
also use AAV2/9-mediated circHomer1 OE in the cortex and hippocampus of 5XFAD and MAPT-P301S mice.
We recently found that seven-month-old 5XFAD mice display significant reductions of circHomer1 expression,
similar to the postmortem brains of AD patients. We will restore circHomer1 levels in the hippocampus and cortex
of 5XFAD and P301S mice using AAV2/9 vectors. This proposal will be the first to systematically analyze the
role of brain and blood circRNAs in AD and to perform in vitro and in vivo functional studies to characterize the
role of circRNAs in AD.
抽象的
临床和生物医学研究中的转录组研究主要集中于线性转录本的变化
提供有关疾病涉及的基因和共表达网络的知识。但是,很少
关于循环RNA(CIRCRNA)在阿尔茨海默氏病(AD)中的作用。 Circrnas是一个新颖的类别
源自前MRNA外显子和内含子的后拼图和共价连接的非编码RNA的数量。我们
最近,从更多
来自两个独立和大型群偶发性的AD病例的621个大脑样本,
无神经病理学的个体。我们确定了与AD相关的特定CIRCRNA,包括Circhomer1
风险和神经病理学特征。该项目将使用脑组织来识别涉及的其他脑circrnas
在我们先前研究中比队列大四倍的队列中的AD中。我们还计划调查
与对照组相比,在AD病例中差异表达的血液CIRCRNA确定其生物标志物实用程序
用于创建新的预测模型。我们将建立一个体外和体内功能的框架
CircrNA在AD中的作用的表征。作为原则的证明,我们将首先定义
circhomer1在与广告相关的基因表达和相关的细胞表型中。我们发现Circhomer1
在诱导的多能干细胞(IPSC)衍生的神经元中高度表达。我们将使用CRISPR/CAS9敲门
在IPSC衍生的神经元中使用circhomer1并使用circhomer1过表达(OE)
来自APP,PSEN1,PSEN2,
和MAPT基因。为了确定circhomer1是否在体内加速/增加与广告相关的病理,我们将
生成Circhomer1-Knockout转基因小鼠,并用5xFAD和MAPT-P301S小鼠交叉。我们将
还要在5xFAD和MAPT-P301S小鼠的皮层中使用AAV2/9介导的Circhomer1 OE。
我们最近发现,七个月大的5xFAD小鼠显示出明显的circhomer1表达降低,
类似于AD患者的后大脑。我们将恢复海马和皮质中的Circhomer1水平
使用AAV2/9矢量的5xFAD和P301S小鼠的组合。该提案将是第一个系统地分析的提案
大脑和血液ciRCRNA在AD中的作用,并在体外和体内功能研究中表征
Circrnas在AD中的作用。
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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Carlos Cruchaga其他文献
Carlos Cruchaga的其他文献
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{{ truncateString('Carlos Cruchaga', 18)}}的其他基金
Identification and Characterization of Cell-Specific Transposable Elements Implicated on Alzheimer Disease and Healthy Aging
与阿尔茨海默病和健康衰老相关的细胞特异性转座元件的鉴定和表征
- 批准号:
10518934 - 财政年份:2022
- 资助金额:
$ 226.52万 - 项目类别:
Identification and Characterization of Cell-Specific Transposable Elements Implicated on Alzheimer Disease and Healthy Aging
与阿尔茨海默病和健康衰老相关的细胞特异性转座元件的鉴定和表征
- 批准号:
10677894 - 财政年份:2022
- 资助金额:
$ 226.52万 - 项目类别:
Genetic Architecture of Alzheimer’s disease Proteinopathies
阿尔茨海默病的遗传结构 蛋白质病
- 批准号:
9995650 - 财政年份:2021
- 资助金额:
$ 226.52万 - 项目类别:
Genetic Architecture of Alzheimer’s disease Proteinopathies
阿尔茨海默病的遗传结构 蛋白质病
- 批准号:
10391426 - 财政年份:2021
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THE GENETICS AND MULTI-OMICS SPECIMENS CORE (GMSC)
遗传学和多组学样本核心 (GMSC)
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10283067 - 财政年份:2021
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THE GENETICS AND MULTI-OMICS SPECIMENS CORE (GMSC)
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10673899 - 财政年份:2021
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Genetic Architecture of Alzheimer’s disease Proteinopathies
阿尔茨海默病的遗传结构 蛋白质病
- 批准号:
10581599 - 财政年份:2021
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Brain Single-nuclei and iPS-derived cells transcriptomic analysis to define the contribution of neuronal and glial pathw
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Genetic Architecture of Alzheimer’s disease Proteinopathies
阿尔茨海默病的遗传结构 蛋白质病
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10532581 - 财政年份:2021
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