No Cell Left Behind: Using Embryoid Bodies to Understand Human Biology
不遗余力:利用胚胎体来了解人类生物学
基本信息
- 批准号:10651667
- 负责人:
- 金额:$ 16.4万
- 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:2022-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdultAffectAutopsyBiologicalCardiac MyocytesCell Culture TechniquesCell LineCellsCollectionComplexControlled EnvironmentDNADataDevelopmentDevelopmental ProcessDiseaseEmbryoEnvironmentEthicsEventFunding OpportunitiesGene ExpressionGene Expression RegulationGenesGeneticGenetic DiseasesGenetic VariationGenomicsGenotype-Tissue Expression ProjectGerm LayersGoalsHepatocyteHumanHuman BiologyHuman bodyIn VitroIndividualLearningLeftMapsMeasuresModelingNeuronsNucleic Acid Regulatory SequencesOrganoidsPhenotypePreparationProcessQuantitative Trait LociResearch DesignResourcesSample SizeSamplingSourceStem cell pluripotencySuggestionSystemTestingTimeTissuesTransformed Cell LineUntranslated RNAVariantcell typedesigndifferentiation protocoldirected differentiationdisorder riskexperimental studygenetic variantgenome wide association studyhuman diseasehuman tissueinduced pluripotent stem cellinter-individual variationnovel strategiespower analysisresponsesingle cell technologysingle-cell RNA sequencingstem cell biologystem cell differentiationstem cellstemporal measurementtheoriestraitunethical
项目摘要
Abstract
This is a revised R21 proposal submitted in response to funding opportunity announcement PA-18-867, “Novel
Approaches for Relating Genetic Variation to Function and Disease”.
Most of the genetic variants that are associated with disease lie within non-coding DNA and are thought to
affect gene regulation. This has inspired efforts to identify variants that affect gene expression levels (eQTLs)
in a wide range of adult tissues. However, most disease-associated SNPs – though they are located in
putatively regulatory regions – have not been found to be eQTLs. One reason for this could be that despite
large-scale efforts to map eQTLs in diverse sets of tissues (e.g, GTEx), we still have not yet examined gene
regulation in the cell types or states most relevant for disease. Many human tissues and cell types, especially
those that are present in early development, are inaccessible due to practical or ethical constraints. Thus, the
pace of genetic discovery is fundamentally limited by access to relevant human tissues.
The discovery that mature human cells can be transformed into stem cells was an important step toward
solving this problem. Induced pluripotent stem cells (iPSCs) provide a renewable source of human tissue that
can, in theory, develop into any cell type. In practice, however, it can take years to discover how to produce
any single tissue from iPSCs using directed differentiation.
At the nexus of stem cell biology and emerging single-cell technologies, there is an opportunity to generate and
study many, or even most, human cell types simultaneously, all within a single dish. When grown in the proper
conditions, stem cells form spontaneously differentiating organoids known as embryoid bodies (EBs). Cells
within EBs differentiate asynchronously into cell types originating from all three germ layers, including
pluripotent, intermediate, and mature cell types. By applying single-cell RNA-sequencing (scRNA-seq) to cells
within EBs, we can jointly identify eQTLs across a multitude of cell types, all within a controlled genetic
environment. The use of EBs will also allow us to observe cellular transitions and regulatory events that are not
evident in static cell culture.
摘要
这是为回应资助机会公告PA-18-867而提交的修订后的R21提案
将遗传变异与功能和疾病联系起来的方法“。
大多数与疾病相关的遗传变异存在于非编码DNA中,并被认为是
影响基因调控。这激发了人们寻找影响基因表达水平(EQTL)的变异的努力
在各种各样的成人组织中。然而,大多数与疾病相关的SNPs-尽管它们位于
假定是受调控的区域-尚未发现eQTL。造成这种情况的一个原因可能是尽管
在不同组织(如GTEx)中定位eQTL的大规模努力,我们仍然没有检测到基因
对与疾病最相关的细胞类型或状态的调节。许多人体组织和细胞类型,特别是
那些出现在早期发展阶段的,由于实际或道德限制而无法接触到。因此,
基因发现的速度从根本上受到获得相关人体组织的限制。
人类成熟细胞可以转化为干细胞的发现是迈向
解决这个问题。诱导多能干细胞(IPSCs)提供了一种可再生的人类组织来源
从理论上讲,可以发育成任何类型的细胞。然而,在实践中,可能需要数年时间才能发现如何生产
使用定向分化技术从IPSCs中获得的任何单个组织。
在干细胞生物学和新兴的单细胞技术的结合点上,有机会产生和
同时研究许多甚至大多数人类细胞类型,所有这些都在一个培养皿中进行。当在适当的地方生长时
在这种情况下,干细胞会自发形成被称为类胚体(EBS)的分化器官。单元格
在EBS内异步分化为起源于所有三个生殖层的细胞类型,包括
多能细胞、中间细胞和成熟细胞类型。通过将单细胞RNA测序(scRNA-seq)应用于细胞
在eBS中,我们可以联合识别多种细胞类型的eQTL,所有这些都在受控的基因范围内
环境。EBS的使用还将使我们能够观察到细胞的转变和调控事件
在静态细胞培养中很明显。
项目成果
期刊论文数量(0)
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Yoav Gilad其他文献
Yoav Gilad的其他文献
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{{ truncateString('Yoav Gilad', 18)}}的其他基金
No Cell Left Behind: Using Embryoid Bodies to Understand Human Biology
不遗余力:利用胚胎体来了解人类生物学
- 批准号:
10427990 - 财政年份:2022
- 资助金额:
$ 16.4万 - 项目类别:
Development of iPSCs for comparative genomics in primates
灵长类动物比较基因组学 iPSC 的开发
- 批准号:
10514213 - 财政年份:2021
- 资助金额:
$ 16.4万 - 项目类别:
Characterizing and Understanding Variation in Gene Regulatory Mechanisms Within and Between Species'
表征和理解物种内部和物种之间基因调控机制的变异
- 批准号:
10405511 - 财政年份:2019
- 资助金额:
$ 16.4万 - 项目类别:
Development of iPSCs for comparative genomics in primates
灵长类动物比较基因组学 iPSC 的开发
- 批准号:
10005952 - 财政年份:2019
- 资助金额:
$ 16.4万 - 项目类别:
Characterizing and Understanding Variation in Gene Regulatory Mechanisms Within and Between Species'
表征和理解物种内部和物种之间基因调控机制的变异
- 批准号:
10626752 - 财政年份:2019
- 资助金额:
$ 16.4万 - 项目类别:
Development of iPSCs for comparative genomics in primates
灵长类动物比较基因组学 iPSC 的开发
- 批准号:
10428553 - 财政年份:2019
- 资助金额:
$ 16.4万 - 项目类别:
Development of iPSCs for comparative genomics in primates
灵长类动物比较基因组学 iPSC 的开发
- 批准号:
10189681 - 财政年份:2019
- 资助金额:
$ 16.4万 - 项目类别:
Characterizing and Understanding Variation in Gene Regulatory Mechanisms Within and Between Species'
表征和理解物种内部和物种之间基因调控机制的变异
- 批准号:
10166610 - 财政年份:2019
- 资助金额:
$ 16.4万 - 项目类别:
Development of iPSCs for comparative genomics in primates
灵长类动物比较基因组学 iPSC 的开发
- 批准号:
10655911 - 财政年份:2019
- 资助金额:
$ 16.4万 - 项目类别:
Mapping eQTLs that affect susceptibility to Tuberculosis
绘制影响结核病易感性的 eQTL
- 批准号:
8417751 - 财政年份:2011
- 资助金额:
$ 16.4万 - 项目类别:
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