A single cell pooling framework for deciphering the regulatory wiring of allergy in pathophysiologic contexts
用于破译病理生理背景下过敏调节线路的单细胞池框架
基本信息
- 批准号:10246100
- 负责人:
- 金额:$ 141.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-23 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAllergensAllergicAllergy to peanutsAsthmaAutopsyBiologicalBiological AssayBiologyBloodBlood specimenCatalogsCaucasiansCell LineCellsChildComplexDeveloped CountriesDiseaseEczemaEnvironmental Risk FactorEtiologyFood HypersensitivityGene ExpressionGene Expression RegulationGenesGeneticGenetic RiskGenomeGenotype-Tissue Expression ProjectHay feverHeritabilityHumanHuman PathologyHuman ResourcesHypersensitivityIncidenceIndividualLifeLinkMapsMediator of activation proteinMethodsMolecularNaturePathway interactionsPatientsPlayPopulationReactionRegulator GenesRiskRoleSchoolsSpecimenStimulusTissuesUntranslated RNAWorkWorld Healthbiobankcausal variantcell typeclinical subtypesfollow-upgenetic variantgenome wide association studygenomic locushuman diseasehuman tissueinnovationmultiple omicspreventrisk variant
项目摘要
Allergy is a major world health challenge affecting 25% of people with a rising incidence. Peanut allergy
alone affects 2.2% of school children in the US and can be life-threatening. Allergy is a complex disease, with
both genetic and environmental factors contributing to risk. In order to pinpoint the underlying genetic risk
variants, genome-wide association studies (GWAS) have been performed on hundreds of thousands of
patients and controls, identifying >100 associated loci. The vast majority of hits are in poorly annotated
noncoding regions of the genome and are thought to influence gene regulation. A major challenge for
understanding allergy (and all complex diseases) is pinpointing the causal variant(s) and defining molecular
mechanisms. The extensive follow up work required is often not undertaken and thus allergy GWAS rarely
contribute to our understanding of disease etiology. In order to mine the rich resource of human disease
associations, new methods are needed to systematically annotate regulatory effects. Existing catalogs are
sparse and biased toward specific cell types (blood), contexts (steady state conditions), molecular
mechanisms (perturbation of gene expression), and populations (Caucasians). Given the highly cell type and
context specific nature of gene regulation, this limited window is unlikely to be sufficient for identifying
most human risk variants. The most comprehensive effort to date to map regulatory effects is the Genotype-
Tissue Expression Project (GTEx), which mapped loci that influence gene expression (eQTLs) in 54 tissues
using autopsy specimens from hundreds of healthy individuals. Despite its scope, the GTEx catalog thus far
explains only 11% of the genetic risk of complex disease, suggesting additional assays and specimens are
needed to unearth the majority of regulatory effects contributing to disease. In this application I propose an
innovative approach to systematically catalog the gene regulatory effects of genetic variants on a massive
scale across diverse allergy-relevant cell types and patient specimens. Crucially, this scalable approach can
accommodate cell stimulation conditions (e.g., allergen challenge), inclusion of diverse human ancestry
groups, and is deployable on scant human tissue and blood specimens. By leveraging a single cell
framework, we are able to probe rare cell populations that play essential roles as mediators of disease. I will
apply this method to allergy relevant GTEx tissues as well as a large-scale allergy biobank representing
heterogenous cases. This study is expected to provide a greatly expanded window into the biology of genetic
loci linked to allergy and elucidate the potential of multi-omic single cell approaches, pathophysiological
stimuli, and patient biospecimens to unearth missing complex disease heritability.
过敏是一个主要的世界健康挑战,影响25%的人,发病率不断上升。花生过敏
仅在美国就有2.2%的学龄儿童受到影响,并可能危及生命。过敏是一种复杂的疾病,
遗传和环境因素都是导致风险的因素。为了确定潜在的遗传风险
变异,全基因组关联研究(GWAS)已经在数十万个
患者和对照,鉴定>100个相关基因座。绝大多数的点击率都是在很差的注释
基因组的非编码区,并被认为影响基因调控。面临的一大挑战
了解过敏(和所有复杂的疾病)是查明病因变异和定义分子
机制等所需的广泛的后续工作往往没有进行,因此过敏GWAS很少
有助于我们了解疾病的病因。为了挖掘人类丰富的疾病资源
协会,需要新的方法来系统地注释监管效果。现有的目录是
稀疏和偏向特定细胞类型(血液),背景(稳态条件),分子
机制(基因表达的扰动)和人群(高加索人)。考虑到高细胞类型和
由于基因调控的背景特异性,这个有限的窗口不太可能足以识别
大多数人类风险变体。迄今为止,绘制调控效应的最全面的努力是基因型-
组织表达计划(GTEx),该计划在54个组织中定位了影响基因表达的基因座(eQTL)
使用了数百名健康人的尸检标本尽管其范围,GTEx目录到目前为止
仅解释了复杂疾病遗传风险的11%,这表明额外的检测和标本
需要发掘出导致疾病的大多数调节作用。在本申请中,我提出了一个
创新的方法,系统地编目基因变异对大规模
在不同的过敏相关细胞类型和患者样本中进行扩展。关键是,这种可扩展的方法可以
适应细胞刺激条件(例如,过敏原攻击),包括不同的人类祖先
组,并部署在缺乏人体组织和血液标本。通过利用单个细胞
框架,我们能够探测作为疾病介质发挥重要作用的稀有细胞群。我会
将这种方法应用于过敏相关的GTEx组织以及代表性的大规模过敏生物样本库,
异质病例这项研究有望为遗传学生物学提供一个大大扩展的窗口。
与过敏相关的基因座,并阐明多组单细胞方法,病理生理学
刺激物和患者生物标本,以挖掘缺失的复杂疾病遗传性。
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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maya kasowski其他文献
maya kasowski的其他文献
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{{ truncateString('maya kasowski', 18)}}的其他基金
Identifying Multidimensional Omics Profiles Associated with Cardiovascular and Pulmonary Responses to Chronic and Acute Air Pollution Exposure (Project 2) for AIRHEALTH Study
确定与慢性和急性空气污染暴露的心血管和肺部反应相关的多维组学概况(项目 2),用于空气健康研究
- 批准号:
10684171 - 财政年份:2021
- 资助金额:
$ 141.66万 - 项目类别:
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