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
基本信息
- 批准号:10607814
- 负责人:
- 金额:$ 78.61万
- 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:2023-02-01 至 2028-01-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAddressAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease riskAmyloid beta-ProteinAtlasesAutopsyBiological AssayBlood VesselsBrainBrain regionCOVID-19 pandemicCRISPR interferenceCell CommunicationCell SurvivalCellsCentral Nervous SystemCoculture TechniquesComplexComputing MethodologiesCytomegalovirusCytomegalovirus InfectionsDataData SetDementiaDevelopmentDiseaseDisease ProgressionDissectionEnvironmental ImpactEtiologyFamilyFoundationsGene Expression ProfileGene Expression ProfilingGene Expression RegulationGenesGeneticGenetic RiskGenetic TranscriptionGoalsHealthcareHerpesvirus 1HippocampusHumanImmuneImmune responseImpaired cognitionIndividualInfectionInterventionJointsLifeLinkMapsMediatingMemory LossMessenger RNAMicrogliaModelingMolecularMolecular Mechanisms of ActionMusNeurodegenerative DisordersNeuronsOrganoidsPathogenicityPathologicPathway interactionsPhenotypePost-Translational Protein ProcessingRegulatory ElementResearchResolutionResourcesRoleSamplingSeveritiesSimplexvirusTestingTranscription AlterationValidationVirusabeta depositionantimicrobial peptidebasebrain cellcare burdencausal variantcell typecerebrovasculardata integrationfrontal lobegenetic risk factorinduced pluripotent stem cellneuroinflammationnovel therapeuticspathogenpersonalized medicinepersonalized therapeuticprotein expressionrisk variantsexsingle nucleus RNA-sequencingsingle-cell RNA sequencingsmall molecule therapeutics
项目摘要
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder that leads to dramatic effects on the affected
individuals and their families. While the characterization of the genetic contribution to AD and underlying
molecular mechanisms has advanced the understanding of the disease in recent years, studies have failed to
find definitive mechanisms that account for disease progression. The influence of pathogens on AD potentially
mediates an environmental impact on the established genetic contributions to AD. Here, we directly dissect the
contribution of pathogen-related effects down to the cell-type-specific molecular basis by systematic profiling,
computational integration, and experimental validation of the transcriptional signatures across individuals, brain
regions, and cell types. In Aim 1, we use scRNA-seq in human, mouse, and human iPSC brain organoid samples of
AD that are infected with Herpes Simplex Virus 1 or Cytomegalovirus (HSV-1/CMV) to generate millions of single-
cell (sc) level maps with the end goal of a transcriptional atlas. In Aim 2, we analyze the resulting datasets and
underlying molecular mechanisms, enabling us to discover and converge genes, pathways, cell types, and
brain regions to functional and causal mechanisms that drive pathogen-related alterations. In Aim 3, we use
our well-established iPSC model to test our predicted mechanisms with both high-throughput and cell-type
specific assays. The resulting datasets, computational predictions, and experimentally-supported mechanisms
will shed light on the pathogen-related influences on AD pathology and will help deepen our understanding of
the disease in general as we develop more personalized therapeutic approaches to treating AD.
摘要
阿尔茨海默氏病(AD)是一种神经退行性疾病,导致戏剧性的影响,受影响的
个人及其家庭。虽然对AD的遗传贡献的表征和潜在的
近年来,分子机制已经推进了对疾病的理解,但研究未能
找到导致疾病进展的确切机制。病原体对AD的潜在影响
介导了环境对AD遗传贡献的影响。在这里,我们直接解剖
病原体相关效应的贡献下至细胞类型特异性分子基础,通过系统分析,
计算集成以及个体、大脑转录特征的实验验证
区域和细胞类型。在目标1中,我们在人类、小鼠和人类iPSC脑类器官样品中使用scRNA-seq,
AD感染单纯疱疹病毒1型或巨细胞病毒(HSV-1/CMV),产生数百万个单-
细胞(SC)水平映射,最终目标是转录图谱。在目标2中,我们分析了产生的数据集,
潜在的分子机制,使我们能够发现和汇聚基因,途径,细胞类型,
大脑区域的功能和因果机制,驱动病原体相关的变化。在目标3中,我们使用
我们完善的iPSC模型,以测试我们预测的机制与高通量和细胞类型
具体分析。由此产生的数据集,计算预测和实验支持的机制
将揭示AD病理学的病原体相关影响,并将有助于加深我们对AD的理解。
随着我们开发更个性化的治疗方法来治疗AD,
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:
$ 78.61万 - 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:
$ 78.61万 - 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:
$ 78.61万 - 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:
$ 78.61万 - 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:
$ 78.61万 - 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:
$ 78.61万 - 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:
$ 78.61万 - 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:
10177837 - 财政年份:2018
- 资助金额:
$ 78.61万 - 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:
$ 78.61万 - 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:
$ 78.61万 - 项目类别:
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