Single-cell epigenomic roadmap of Alzheimer's disease
阿尔茨海默病的单细胞表观基因组路线图
基本信息
- 批准号:10390136
- 负责人:
- 金额:$ 4.19万
- 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:2022-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAgeAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease patientAlzheimer&aposs disease riskAmyloid beta-ProteinAtlasesAxonBindingBiologicalBiological AssayBiologyBrainBrain regionCRISPR/Cas technologyCell NucleusCellsChromatinCognitiveCommunitiesComplexConsensusCritical PathwaysDataData SetDevelopmentDiseaseDisease associated microgliaDisease susceptibilityDistal Enhancer ElementsEnhancersEnvironmental Risk FactorEvaluationFutureGene ExpressionGenesGenetic Enhancer ElementGenetic RiskGenetic VariationGenomic SegmentGliosisHealthHeritabilityHeterogeneityHigh-Throughput Nucleotide SequencingHippocampus (Brain)Impaired cognitionKnock-outLinkMemory LossMeta-AnalysisMethodsMicrogliaMolecularNerve DegenerationNeurodegenerative DisordersNeurogliaNeuronsPathologyPathway AnalysisPathway interactionsPatternPhenotypePopulationPrefrontal CortexPublishingRegulator GenesRegulatory ElementResolutionResourcesRiskRisk FactorsRoleSenile PlaquesSmall Nuclear RNASpecificityStructureSupervisionSystemTREM2 geneTechniquesTherapeuticTransposaseUntranslated RNAValidationVariantWorkbrain cellcell typedeep learningdisorder riskentorhinal cortexepigenomeepigenomicsexperimental studygene interactiongene networkgenetic risk factorgenetic variantgenome wide association studyhealthy aginghuman diseaseinduced pluripotent stem cellmind controlmolecular phenotypemultimodalitypromoterrisk variantsingle cell analysistau aggregationtraittranscription factortranscriptometranscriptome sequencingtranscriptomics
项目摘要
Project Summary/Abstract
Genetic variation drives phenotypic variation across many traits, including heritable risk for disease
susceptibility in neurodegenerative disorders such as Alzheimer’s Disease (AD). For complex polygenic human
diseases, it is difficult to unravel precisely which molecular changes are brought on by genetic risk factors. It is
well known that genetic variants at the APOE locus can confer a neuroprotective status from AD, while another
variant drastically increases one’s chances of developing disease. Even these well studied variants are not
fully understood at the molecular level. The majority of disease-associated risk variants for AD and other
disorders lie in non-coding regulatory elements and are therefore best studied using epigenomic techniques.
Since previous studies have shown that AD affects different brain regions and cell types throughout its
progression, I hypothesize that the mechanisms underlying genetic risk for AD act similarly in a progressive,
region-specific, and cell-type-specific manner. In this proposal, we aim to generate chromatin accessibility
profiles for single cells across the prefrontal cortex, the hippocampus, and the entorhinal cortex of AD patient
brains, and integrate with published single cell transcriptomics data, thereby allowing us to identify enhancer-
gene interactions that are disrupted by AD risk variants. Our preliminary work has shown that microglia-specific
enhancers are enriched for AD genetic risk factors. Therefore, we will use CRISPR-cas9 to delete an enhancer
linked to the variant rs4663105 at the BIN1 locus in induced pluripotent stem cell (iPSC) derived microglia,
thereby allowing us to unravel its role in the regulatory landscape. My preliminary data from the prefrontal
cortex shows that the chromatin accessibility landscape is highly cell-type specific and is significantly altered in
AD patient brains, and I expect that we will find regional specificity of regulatory elements that are disrupted by
AD risk variants. Aside from our specific task of identifying these disease-associated regulatory elements, an
integrated study of single-cell epigenomics and single-cell transcriptomics data in AD brains will be of great
value to the broader AD community to further implicate genes, networks, and pathways as targets for future
studies.
项目总结/摘要
遗传变异驱动许多性状的表型变异,包括疾病的遗传风险
神经退行性疾病如阿尔茨海默病(AD)的易感性。对于复杂的多基因人类
虽然我们对疾病的研究很深入,但很难准确地阐明哪些分子变化是由遗传风险因素引起的。是
众所周知,APOE基因座的遗传变异可以赋予AD的神经保护状态,而另一个基因则可以赋予AD的神经保护状态。
变异大大增加了一个人患病的机会。即使是这些经过充分研究的变体,
在分子水平上完全被理解。AD和其他疾病的大多数疾病相关风险变异
疾病在于非编码调节元件,因此最好使用表观基因组技术进行研究。
由于先前的研究表明,AD影响不同的大脑区域和细胞类型,
进展,我假设AD遗传风险的潜在机制在进行性,
区域特异性和细胞类型特异性方式。在这个建议中,我们的目标是产生染色质可及性
AD患者前额叶皮层、海马和内嗅皮层的单细胞分布图
大脑,并与已发表的单细胞转录组学数据相结合,从而使我们能够识别增强子-
基因相互作用被AD风险变体破坏。我们的初步工作表明,
增强子富集AD遗传风险因子。因此,我们将使用CRISPR-cas9来删除增强子,
与诱导多能干细胞(iPSC)衍生的小胶质细胞中BIN 1基因座处的变体rs 4663105连锁,
从而使我们能够了解它在监管领域的作用。我从大脑前额叶提取的初步数据
皮质显示,染色质可及性景观是高度细胞类型特异性的,并在
AD患者的大脑中,我希望我们会发现区域特异性的调节元件,被破坏,
AD风险变体。除了我们确定这些疾病相关调控元件的具体任务外,
AD脑中单细胞表观基因组学和单细胞转录组学数据的综合研究将具有重要意义。
更广泛的AD社区的价值,以进一步牵连基因,网络和途径作为未来的目标
问题研究
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Samuel Joseph Morabito其他文献
Samuel Joseph Morabito的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Samuel Joseph Morabito', 18)}}的其他基金
Single-cell epigenomic roadmap of Alzheimer's disease
阿尔茨海默病的单细胞表观基因组路线图
- 批准号:
10710408 - 财政年份:2022
- 资助金额:
$ 4.19万 - 项目类别:
相似国自然基金
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
- 批准号:JCZRQN202500010
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
- 批准号:2025JJ70209
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
- 批准号:
- 批准年份:2024
- 资助金额:0 万元
- 项目类别:面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
- 批准号:2023JJ50274
- 批准年份:2023
- 资助金额:0.0 万元
- 项目类别:省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
- 批准号:
- 批准年份:2022
- 资助金额:33 万元
- 项目类别:地区科学基金项目
补肾健脾祛瘀方调控AGE/RAGE信号通路在再生障碍性贫血骨髓间充质干细胞功能受损的作用与机制研究
- 批准号:
- 批准年份:2022
- 资助金额:52 万元
- 项目类别:面上项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
- 批准号:n/a
- 批准年份:2022
- 资助金额:10.0 万元
- 项目类别:省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
- 批准号:81973577
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
- 批准号:81602908
- 批准年份:2016
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
- 批准号:81501928
- 批准年份:2015
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
相似海外基金
PROTEMO: Emotional Dynamics Of Protective Policies In An Age Of Insecurity
PROTEMO:不安全时代保护政策的情绪动态
- 批准号:
10108433 - 财政年份:2024
- 资助金额:
$ 4.19万 - 项目类别:
EU-Funded
The role of dietary and blood proteins in the prevention and development of major age-related diseases
膳食和血液蛋白在预防和发展主要与年龄相关的疾病中的作用
- 批准号:
MR/X032809/1 - 财政年份:2024
- 资助金额:
$ 4.19万 - 项目类别:
Fellowship
Atomic Anxiety in the New Nuclear Age: How Can Arms Control and Disarmament Reduce the Risk of Nuclear War?
新核时代的原子焦虑:军控与裁军如何降低核战争风险?
- 批准号:
MR/X034690/1 - 财政年份:2024
- 资助金额:
$ 4.19万 - 项目类别:
Fellowship
Collaborative Research: Resolving the LGM ventilation age conundrum: New radiocarbon records from high sedimentation rate sites in the deep western Pacific
合作研究:解决LGM通风年龄难题:西太平洋深部高沉降率地点的新放射性碳记录
- 批准号:
2341426 - 财政年份:2024
- 资助金额:
$ 4.19万 - 项目类别:
Continuing Grant
Collaborative Research: Resolving the LGM ventilation age conundrum: New radiocarbon records from high sedimentation rate sites in the deep western Pacific
合作研究:解决LGM通风年龄难题:西太平洋深部高沉降率地点的新放射性碳记录
- 批准号:
2341424 - 财政年份:2024
- 资助金额:
$ 4.19万 - 项目类别:
Continuing Grant
Walkability and health-related quality of life in Age-Friendly Cities (AFCs) across Japan and the Asia-Pacific
日本和亚太地区老年友好城市 (AFC) 的步行适宜性和与健康相关的生活质量
- 批准号:
24K13490 - 财政年份:2024
- 资助金额:
$ 4.19万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Discovering the (R)Evolution of EurAsian Steppe Metallurgy: Social and environmental impact of the Bronze Age steppes metal-driven economy
发现欧亚草原冶金的(R)演变:青铜时代草原金属驱动型经济的社会和环境影响
- 批准号:
EP/Z00022X/1 - 财政年份:2024
- 资助金额:
$ 4.19万 - 项目类别:
Research Grant
ICF: Neutrophils and cellular senescence: A vicious circle promoting age-related disease.
ICF:中性粒细胞和细胞衰老:促进与年龄相关疾病的恶性循环。
- 批准号:
MR/Y003365/1 - 财政年份:2024
- 资助金额:
$ 4.19万 - 项目类别:
Research Grant
Doctoral Dissertation Research: Effects of age of acquisition in emerging sign languages
博士论文研究:新兴手语习得年龄的影响
- 批准号:
2335955 - 财政年份:2024
- 资助金额:
$ 4.19万 - 项目类别:
Standard Grant
Shaping Competition in the Digital Age (SCiDA) - Principles, tools and institutions of digital regulation in the UK, Germany and the EU
塑造数字时代的竞争 (SCiDA) - 英国、德国和欧盟的数字监管原则、工具和机构
- 批准号:
AH/Y007549/1 - 财政年份:2024
- 资助金额:
$ 4.19万 - 项目类别:
Research Grant