Topographic, cell type and molecular pathway characterization ofAlzheimer's disease using single cell transcriptomics and epigenomics
使用单细胞转录组学和表观基因组学对阿尔茨海默病进行地形、细胞类型和分子途径表征
基本信息
- 批准号:10612891
- 负责人:
- 金额:$ 605.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AdultAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease pathologyAmyloid beta-ProteinAntibodiesAppearanceAutopsyBiologyBrainBrain regionCell NucleusCellsChromatinClassificationClinicalCognitionCommunitiesDataData SetDatabasesDementiaDiseaseDisease ProgressionEpigenetic ProcessFunctional disorderFutureGene ExpressionGene Expression ProfileGenesGeneticGenetic TranscriptionGliosisGoalsIndividualLinkMapsMeasurementMemoryMethodsMethylationModificationMolecularNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNuclearPathogenesisPathologicPathologyPathway interactionsPatternPhasePhenotypePopulationPredispositionProcessProtocols documentationRNARegulator GenesResistanceResolutionResourcesSamplingSeveritiesSeverity of illnessSortingSpecificityStagingStandardizationStereotypingStructureSurveysTechniquesTimeTissuesamyloid pathologybrain tissuecell typecohortcomorbiditycostdesigndisease diagnosisdisease phenotypedisorder subtypedrug discoveryepigenomicsextracellularfollow-upgene networkhyperphosphorylated tauinsightmisfolded proteinmultiple omicsneuron lossneuropathologynext generationnormal agingprogressive neurodegenerationsingle nucleus RNA-sequencingsuccesstau Proteinstau aggregationtranscriptomics
项目摘要
ABSTRACT (PROJECT 2)
Alzheimer's disease (AD) is a highly penetrant neurodegenerative disease projected to affect 13.8 million
cases in the US by 2050 at a cost of $1.1 trillion if no treatment is developed. AD is characterized by stereotyped
progressive neurodegeneration and accumulation of two misfolded proteins in brain regions important for
cognition and memory. Neurofibrillary tangles (NFTs) of hyperphosphorylated tau follow a progression like
neurodegeneration, while extracellular amyloid beta (Aβ) plaques are initially detected in cortical and deep brain
structures. It is unclear whether these pathologies are causal or effects of other underlying processes and
currently no anti-tau or anti- Aβ therapies stop or reverse AD. Gene expression studies of AD have largely been
performed on tissue or cell populations, and impact of neuronal loss and gliosis on these results is unknown.
Epigenetic modifications are also associated with AD, though methylation studies have produced conflicting
results and no clear pattern of epigenetic dysregulation associated directly with AD progression has emerged.
The present study adapts recently developed high-throughput, single-cell methods for transcriptomic and
epigenetic analysis to the identify molecular and gene regulatory hallmarks of “clinically typical” AD without
significant co-morbidities. Building off a detailed understanding of neurotypical adult cell types, the project aims
to identify transcriptional changes in specific cell types or classes correlated with increasing severity of AD
pathology in different brain regions affected by the disease, and then identify gene and chromatin accessibility
changes with pathology in vulnerable cell populations. This project will initially optimize single nucleus RNA-seq
and epigenetics methods for use with postmortem samples of varying pathology and tissue quality, and generate
reference datasets for brain regions to be analyzed in AD. Low-cost, droplet-based single nucleus RNA-seq will
then be used to classify and characterize cell types in regions differentially affected by tau and amyloid pathology
from many donors spanning AD progression with quantified tau and Aβ pathologies. A broader set of brain
regions will then be surveyed on a subset of cases with consistent AD-related phenotypes to understand whether
there is a common AD signature across brain regions, and whether signatures of AD can be detected prior to
the emergence of neuropathology. Finally, higher-resolution methods will target transcriptomic and epigenetic
changes in AD associated with pathology and disease diagnosis in specific cell types, aimed at achieving a
mechanistic understanding of AD phenotypes. Using this design, this project can directly probe dysregulated
gene networks within affected cell types for the first time, providing a potential causal link between genetic or
epigenetic states and resulting gene expression. The resulting datasets and platform will produce valuable
insights into the cellular and molecular basis of AD and will be made publicly accessible through the Data Core.
摘要(项目2)
阿尔茨海默病(AD)是一种高度渗透性的神经退行性疾病,预计影响1380万人
到2050年,如果不开发治疗方法,美国将花费1.1万亿美元。AD的特征是刻板的
进行性神经变性和两种错误折叠的蛋白质在大脑区域的积累,
认知和记忆。过度磷酸化tau蛋白的神经元缠结(NFT)遵循以下进展,
神经变性,而细胞外淀粉样蛋白β(Aβ)斑块最初在皮质和深部脑中检测到
结构.目前尚不清楚这些病理是因果关系还是其他潜在过程的影响,
目前没有抗tau或抗Aβ疗法停止或逆转AD。AD的基因表达研究主要是
在组织或细胞群上进行,并且神经元损失和神经胶质增生对这些结果的影响是未知的。
表观遗传修饰也与AD相关,尽管甲基化研究产生了相互矛盾的结果,
结果表明,没有出现与AD进展直接相关的表观遗传失调的明确模式。
本研究采用了最近开发的高通量,单细胞的转录组学方法,
表观遗传分析,以确定“临床典型”AD的分子和基因调控标志,
显著的合并症。建立在对神经典型成体细胞类型的详细了解基础上,该项目旨在
鉴定与AD严重程度增加相关的特定细胞类型或类别中的转录变化
病理在不同的大脑区域受疾病影响,然后确定基因和染色质的可及性
脆弱细胞群的病理变化。该项目将初步优化单核RNA-seq
和表观遗传学方法用于不同病理学和组织质量的死后样品,并产生
用于在AD中分析的脑区域的参考数据集。低成本、基于液滴的单核RNA-seq将
然后用于分类和表征受tau和淀粉样蛋白病理学差异影响的区域中的细胞类型
来自许多跨越AD进展的供体,具有定量的tau和Aβ病理。更广泛的大脑
然后将对具有一致AD相关表型的病例子集进行调查,以了解是否
在整个大脑区域中存在共同的AD特征,以及是否可以在治疗之前检测到AD的特征。
神经病理学的出现最后,更高分辨率的方法将针对转录组和表观遗传
与特定细胞类型的病理学和疾病诊断相关的AD变化,旨在实现
对AD表型的机械理解。使用这种设计,本项目可以直接探测失调
第一次在受影响的细胞类型内的基因网络,提供了遗传或
表观遗传状态和由此产生的基因表达。由此产生的数据集和平台将产生有价值的
深入了解AD的细胞和分子基础,并将通过Data Core公开访问。
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 }}
Ed Lein其他文献
Ed Lein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('Ed Lein', 18)}}的其他基金
Functionally guided adult whole brain cell atlas in human and NHP
人类和 NHP 的功能引导成人全脑细胞图谱
- 批准号:
10687245 - 财政年份:2022
- 资助金额:
$ 605.46万 - 项目类别:
Functionally guided adult whole brain cell atlas in human and NHP
人类和 NHP 的功能引导成人全脑细胞图谱
- 批准号:
10523848 - 财政年份:2022
- 资助金额:
$ 605.46万 - 项目类别:
Spatial analysis of regional, cell type and molecular hallmarks of Alzheimer's disease
阿尔茨海默病的区域、细胞类型和分子标志的空间分析
- 批准号:
10612895 - 财政年份:2020
- 资助金额:
$ 605.46万 - 项目类别:
Spatial analysis of regional, cell type and molecular hallmarks of Alzheimer's disease
阿尔茨海默病的区域、细胞类型和分子标志的空间分析
- 批准号:
10375363 - 财政年份:2020
- 资助金额:
$ 605.46万 - 项目类别:
Organization and architecture of a Center for cellular resolution analysis of Alzheimer's disease
阿尔茨海默病细胞分辨率分析中心的组织和架构
- 批准号:
10112798 - 财政年份:2020
- 资助金额:
$ 605.46万 - 项目类别:
Spatial analysis of regional, cell type and molecular hallmarks of Alzheimer's disease
阿尔茨海默病的区域、细胞类型和分子标志的空间分析
- 批准号:
10112806 - 财政年份:2020
- 资助金额:
$ 605.46万 - 项目类别:
Topographic, cell type and molecular pathway characterization ofAlzheimer's disease using single cell transcriptomics and epigenomics
使用单细胞转录组学和表观基因组学对阿尔茨海默病进行地形、细胞类型和分子途径表征
- 批准号:
10112803 - 财政年份:2020
- 资助金额:
$ 605.46万 - 项目类别:
Organization and architecture of a Center for cellular resolution analysis of Alzheimer's disease
阿尔茨海默病细胞分辨率分析中心的组织和架构
- 批准号:
10375358 - 财政年份:2020
- 资助金额:
$ 605.46万 - 项目类别:
Topographic, cell type and molecular pathway characterization ofAlzheimer's disease using single cell transcriptomics and epigenomics
使用单细胞转录组学和表观基因组学对阿尔茨海默病进行地形、细胞类型和分子途径表征
- 批准号:
10375362 - 财政年份:2020
- 资助金额:
$ 605.46万 - 项目类别:
Organization and architecture of a Center for cellular resolution analysis of Alzheimer's disease
阿尔茨海默病细胞分辨率分析中心的组织和架构
- 批准号:
10612880 - 财政年份:2020
- 资助金额:
$ 605.46万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 605.46万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 605.46万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 605.46万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 605.46万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 605.46万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 605.46万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 605.46万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 605.46万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 605.46万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 605.46万 - 项目类别:
Grant-in-Aid for Early-Career Scientists