Promoter interactome-aided mapping of unexplored CVID genetic landscapes
未探索的 CVID 遗传景观的启动子相互作用组辅助绘图
基本信息
- 批准号:10640143
- 负责人:
- 金额:$ 57.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-16 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalATAC-seqAffinityAntibodiesArchitectureAutoimmune DiseasesB-LymphocytesBLR1 geneBlood specimenCD19 geneCD4 Positive T LymphocytesCatalogingCatalogsCell Differentiation processCell LineCell physiologyCellsCessation of lifeChromatinCoculture TechniquesCodeCombinatoricsCommon Variable ImmunodeficiencyCommunicable DiseasesComplement 3d ReceptorsCopy Number PolymorphismDNADataData SetDiseaseEnvironmentEpigenetic ProcessEuchromatinFosteringFunctional disorderGene ExpressionGenesGeneticGenetic TranscriptionGenetic VariationGenomeGenome MappingsGenomic SegmentGenotypeGoalsGrantHelper-Inducer T-LymphocyteHomeostasisHyperplasiaImmunocompetentImmunoglobulin Class SwitchingImmunoglobulin DImmunologic Deficiency SyndromesIndividualInheritedInvestigationLinkage DisequilibriumLymph Node DissectionsLymphocyteLymphocyte FunctionLymphoid TissueMapsMeasuresMendelian disorderMethodsPathogenesisPathologyPatientsPhenotypePredispositionProteinsProxyPublishingQuantitative Trait LociRNA librarySamplingSentinelSingle Nucleotide PolymorphismSortingSpliced GenesStructureStructure of germinal center of lymph nodeSymptomsT-LymphocyteTechnologyTestingTissuesTonsilTranscriptTranscriptional RegulationUntranslated RNAValidationVariantWorkcell typechromosome conformation captureclinically significantcommon symptomcongenital immunodeficiencyexomegene interactiongenetic variantgenetically modified cellsgenome wide association studygenome-wideinnovationinterleukin-21lymph node biopsylymph nodesnovel diagnosticsnovel therapeuticspersonalized medicineprogramspromoterresponsetranscriptomewhole genome
项目摘要
PROJECT SUMMARY/ABSTRACT
Common variable immunodeficiency (CVID) is a primary disease of germinal center (GC) dysfunction, yet most
CVID mechanistic investigations have utilized patient blood samples, which do not contain bona fide GC cells.
Similarly, genome-wide association studies (GWAS) of CVID patients have identified many disease-associated
single nucleotide polymorphisms (SNPs), yet most lie in non-coding DNA and are of unclear relevance to
disease pathogenesis. The long-range goal of the proposed work is to determine the full genetic basis of CVID.
The objective of this grant is to determine which non-coding regions of DNA contribute to GC dysfunction. The
working hypothesis is that CVID GWAS SNPs point to important non-coding genomic regions that interact with
promoters of genes key to GC lymphocyte function. Further, genetic variation altering gene promoter
interactions, or damage to these genes themselves, will lead to GC dysfunction and eventually the symptoms
of CVID. Our rationale is that identifying gene promoter interactions critical to GC homeostasis will provide new
diagnostic and therapeutic opportunities for patients suffering from diseases of GC dysfunction including, but
not limited to, CVID. Our specific aims will test the following hypotheses: (Aim 1) CVID GWAS associated
regions euchromatically interact with gene promoters in T follicular helper cells (Tfh) and/or follicular B cells
(FO B cells); (Aim 2) these interactions influence gene expression; (Aim 3) non-coding variants altering gene
expression or variants damaging coding genes are enriched in CVID patients and that rhese variants alter Tfh
and FO B cell function. The contribution is significant because cataloguing the genes and gene promoter
contacts vital to GC homeostasis/dysfunction will offer new disease discovery opportunities and provide new
molecules to target with personalized therapies. The proposed work is innovative because we are reinterpreting
published GWAS with a suite of interlocking genome-scale technologies capable of annotating individual SNPs
with overlapping layers of cell type-specific epigenetic information including promoter contacts, chromatin
availability and gene expression. Further, we are verifying our findings in CVID exomes and genomes, with
genetically modified cell-lines, with patient lymph nodes and in co-cultures that recapitulate key transcriptional
features of the GC environment.
项目总结/文摘
项目成果
期刊论文数量(1)
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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NEIL David ROMBERG其他文献
NEIL David ROMBERG的其他文献
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{{ truncateString('NEIL David ROMBERG', 18)}}的其他基金
Promoter interactome-aided mapping of unexplored CVID genetic landscapes
未探索的 CVID 遗传景观的启动子相互作用组辅助绘图
- 批准号:
10207385 - 财政年份:2019
- 资助金额:
$ 57.02万 - 项目类别:
Promoter interactome-aided mapping of unexplored CVID genetic landscapes
未探索的 CVID 遗传景观的启动子相互作用组辅助绘图
- 批准号:
10443566 - 财政年份:2019
- 资助金额:
$ 57.02万 - 项目类别:
Promoter interactome-aided mapping of unexplored CVID genetic landscapes
未探索的 CVID 遗传景观的启动子相互作用组辅助绘图
- 批准号:
9978706 - 财政年份:2019
- 资助金额:
$ 57.02万 - 项目类别:
Blocking autoantibody secretion in CVID patients with ITP by IL-2 restored Tregs
通过 IL-2 阻断 CVID 合并 ITP 患者的自身抗体分泌可恢复 Tregs
- 批准号:
8805484 - 财政年份:2014
- 资助金额:
$ 57.02万 - 项目类别:
BLOCKING AUTOANTIBODY SECRETION IN CVID PATIENTS WITH ITP BY IL-2 RESTORED TREGS
通过 IL-2 恢复的 Tregs 阻断 CVID 患者的自身抗体分泌
- 批准号:
8985654 - 财政年份:2014
- 资助金额:
$ 57.02万 - 项目类别:
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