Elucidating the Molecular Mechanisms of Neuropsychiatric Symptoms in Alzheimer's Disease
阐明阿尔茨海默病神经精神症状的分子机制
基本信息
- 批准号:10177837
- 负责人:
- 金额:$ 129.5万
- 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:2018-09-30 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAffectAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAstrocytesAutopsyBayesian MethodBiologicalBiological ProcessBrainBrain regionCRISPR/Cas technologyCaregiver BurdenCellsChIP-seqClinical ManagementClustered Regularly Interspaced Short Palindromic RepeatsCoculture TechniquesCognitionCommunitiesComputer AnalysisDataData SetDementiaDevelopmentDiseaseDissectionDistalEP300 geneEngineeringEnhancersEtiologyGene ExpressionGene Expression ProfileGenerationsGenesGeneticGenetic TranscriptionGenetic VariationHi-CHippocampus (Brain)Impaired cognitionIndividualKnock-outLinkMapsMeasuresMediationMemoryMethodologyMicrogliaMolecularNeurodegenerative DisordersNeuronsNucleic Acid Regulatory SequencesOligodendrogliaOrganoidsPathologicPathway interactionsPatientsPersonalityPhenotypePrefrontal CortexProcessPsychosesRNARegulatory ElementRepressionRiskSamplingSchizophreniaSeverity of illnessSocial BehaviorSorting - Cell MovementTechniquesTestingTherapeutic InterventionVariantassociated symptombaseburden of illnesscell typedata resourcedifferential expressiondisabilitydisorder controlepigenomicsgenetic informationgenome wide association studygenomic locushealthy aginghuman old age (65+)induced pluripotent stem cellinsightmachine learning methodmolecular scalemortalityneuropsychiatric symptomnovelnovel therapeuticsprogramspromoterpsychotic symptomsrisk variantsingle-cell RNA sequencingtraittranscriptometranscriptomics
项目摘要
Abstract
Alzheimer's disease (AD) is the most common cause of dementia, and the most common neurodegenerative
disease worldwide, affecting 1 in 8 individuals over 65 years old in the US. Within AD, approximately 40-60%
individuals are affected by psychotic symptoms (AD+P), which are associated with more rapid cognitive
decline, greater disability, mortality and caregiver burden, resulting in a disproportionately large disease
burden. Recent studies indicate a genetic basis for AD+P risk, but the molecular basis of AD+P remains largely
uncharacterized, hindering the search for appropriate treatments and novel therapeutics. In this proposal, we
seek to systematically dissect the mechanistic basis of AD+P by systematic generation, integration, and
experimental dissection of transcriptional and epigenomic phenotypes across two brain regions and four cell
types. (1) We profile single-cell RNA-seq and cell-type specific H3K27ac ChIP-seq across 192 post-mortem
brain samples, each in two regions across AD patients with psychosis, AD patients with no psychosis,
schizophrenia patients with no AD, and control individuals. (2) We integrate the resulting datasets with genetic
information and GWAS data to predict driver genes, regions, variants, and pathways underlying AD+P using
state-of-the-art machine learning methods for causality, mediation analysis, and genetic Bayesian fine-
mapping. (3) We use our computational predictions to guide a systematic dissection of the molecular
underpinnings of AD+P using a modular and programmable CRISPR-Cas9 methodology in iPSC lines to
modulate regulatory elements, genes and alleles, and measure the resulting molecular and cellular phenotypes
in cell-autonomous and non-autonomous phenotypes. If successful, this ambitious proposal has the potential
to provide the first mechanistic insights on the development of psychotic symptoms in AD+P and/or P-AD,
reveal functional risk variants and target genes for therapeutic intervention that will likely influence clinical
management in order to alleviate the personal and societal burden associated with these disorders.
摘要
阿尔茨海默病(Alzheimer's disease,AD)是痴呆症最常见的病因,也是最常见的神经退行性疾病,
这种疾病在全球范围内流行,在美国每8个65岁以上的人中就有1个受到影响。在AD中,约40-60%
个体受精神病性症状(AD+P)的影响,这与更快的认知能力有关。
下降,残疾、死亡率和照顾者负担增加,导致疾病不成比例地严重
负担最近的研究表明AD+P风险的遗传基础,但AD+P的分子基础在很大程度上仍然是
这阻碍了对适当治疗和新疗法的探索。在本提案中,我们
寻求通过系统的生成、整合和整合来系统地剖析AD+P的机制基础
跨两个脑区和四个细胞的转录和表观基因组表型的实验解剖
类型(1)我们分析了192例尸检中的单细胞RNA-seq和细胞类型特异性H3 K27 ac ChIP-seq。
大脑样本,每个样本在两个区域中,横跨患有精神病的AD患者,没有精神病的AD患者,
无AD的精神分裂症患者和对照个体。(2)我们将得到的数据集与遗传
信息和GWAS数据来预测AD+P的驱动基因、区域、变体和途径,
用于因果关系、中介分析和遗传贝叶斯精细分析的最先进的机器学习方法,
映射. (3)我们用我们的计算预测来指导分子的系统解剖,
在iPSC系中使用模块化和可编程CRISPR-Cas9方法来支持AD+P,
调节调节元件、基因和等位基因,并测量产生的分子和细胞表型
在细胞自主和非自主表型中。如果成功的话,这个雄心勃勃的计划有可能
提供关于AD+P和/或P-AD中精神病性症状发展的第一个机制见解,
揭示功能性风险变异和治疗干预的靶基因,可能会影响临床
管理,以减轻与这些疾病相关的个人和社会负担。
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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Manolis Kellis其他文献
Manolis Kellis的其他文献
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{{ truncateString('Manolis Kellis', 18)}}的其他基金
Investigating cell-type specific convergence of APOE and ABCA7 lipid dysregulation in Alzheimer’s disease
研究阿尔茨海默病中 APOE 和 ABCA7 脂质失调的细胞类型特异性趋同
- 批准号:
10900993 - 财政年份:2023
- 资助金额:
$ 129.5万 - 项目类别:
Single-cell multi-region dissection of AD-pathogen interactions for HSV-1 and CMV
HSV-1 和 CMV AD 病原体相互作用的单细胞多区域解剖
- 批准号:
10607814 - 财政年份:2023
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$ 129.5万 - 项目类别:
Single-cell epigenomic and trancriptional dissection of sex-specific differences in Alzheimer’s Disease
阿尔茨海默病性别特异性差异的单细胞表观基因组和转录解析
- 批准号:
10495202 - 财政年份:2021
- 资助金额:
$ 129.5万 - 项目类别:
Single-cell epigenomic and trancriptional dissection of sex-specific differences in Alzheimer’s Disease
阿尔茨海默病性别特异性差异的单细胞表观基因组和转录解析
- 批准号:
10300867 - 财政年份:2021
- 资助金额:
$ 129.5万 - 项目类别:
Single-cell epigenomic and trancriptional dissection of sex-specific differences in Alzheimer’s Disease
阿尔茨海默病性别特异性差异的单细胞表观基因组和转录解析
- 批准号:
10633255 - 财政年份:2021
- 资助金额:
$ 129.5万 - 项目类别:
Single-cell transcriptional and epigenomic dissection of Alzheimer's Disease and Related Dementias
阿尔茨海默病和相关痴呆症的单细胞转录和表观基因组解剖
- 批准号:
10011923 - 财政年份:2018
- 资助金额:
$ 129.5万 - 项目类别:
Single-cell transcriptional and epigenomic dissection of Alzheimer's Disease and Related Dementias
阿尔茨海默病和相关痴呆症的单细胞转录和表观基因组解剖
- 批准号:
9791035 - 财政年份:2018
- 资助金额:
$ 129.5万 - 项目类别:
Elucidating the Molecular Mechanisms of Neuropsychiatric Symptoms in Alzheimer's Disease
阐明阿尔茨海默病神经精神症状的分子机制
- 批准号:
10451516 - 财政年份:2018
- 资助金额:
$ 129.5万 - 项目类别:
Interpreting non-coding variants using epigenomics, regulatory models, & validation experiments
使用表观基因组学、调控模型解释非编码变异,
- 批准号:
9616350 - 财政年份:2017
- 资助金额:
$ 129.5万 - 项目类别:
Interpreting non-coding variants using epigenomics, regulatory models, & validati
使用表观基因组学、调控模型解释非编码变异,
- 批准号:
9349567 - 财政年份:2015
- 资助金额:
$ 129.5万 - 项目类别:
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