New computational, transcriptional, and genome editing approaches to the biology of inflammatory bowel disease
研究炎症性肠病生物学的新计算、转录和基因组编辑方法
基本信息
- 批准号:10200800
- 负责人:
- 金额:$ 17.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-19 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAfrican AmericanAllelesAmericanAncillary StudyArchitectureAreaAwardBar CodesBiological AssayBiologyBiopsyBloodCRISPR/Cas technologyCategoriesCellsClinicalClustered Regularly Interspaced Short Palindromic RepeatsComplementComplexCrohn&aposs diseaseCytokine SignalingDNADataData Coordinating CenterData SetDevelopmentDiseaseDisease ProgressionDrug Delivery SystemsEpithelial CellsEthnic OriginEuropeanExtracellular MatrixFoundationsFunctional disorderGene ExpressionGenesGeneticGenetic DiseasesGenetic EngineeringGenetic PolymorphismGenetic RiskGenetic TranscriptionGenomic approachGenomicsGuide RNAHumanImmuneIndividualInflammatory Bowel DiseasesIntestinesKnock-outLaboratoriesLocationMediatingMessenger RNAMitochondriaMolecularNational Institute of Diabetes and Digestive and Kidney DiseasesOrgan Culture TechniquesOrganoidsOutcomePathogenesisPathologyPatient-Focused OutcomesPatientsPharmacologic SubstancePharmacologyPlayProtocols documentationQuantitative GeneticsReagentResearchResearch PersonnelResourcesRiskRisk AssessmentRoleSideSignal TransductionSiteSourceSusceptibility GeneSystemTranscriptTranslatingUlcerative Colitisaptamerbasecausal variantcell typegain of functiongastrointestinal epitheliumgene discoverygene expression variationgene therapygenetic analysisgenetic approachgenetic manipulationgenome editinggenome sequencinggenome wide association studyimprovedin silicoin vivointestinal epitheliumknockout genelipid nanoparticlemRNA deliverymembernanoparticlenanoparticle deliverynovelnovel strategiespatient responserectalresponserisk variantsingle-cell RNA sequencingtherapeutic evaluationtranscriptometranscriptomicstreatment responsewhole genome
项目摘要
Project Summary
Over the past decade, the NIDDK IBDGC (Inflammatory Bowel Disease Genetics Consortium) has
generated extraordinary datasets in support of genetic analysis of the onset, progression, and therapeutic
response to Crohn's disease and ulcerative colitis. This Ancillary project will complement ongoing IBDGC
research by providing parallel statistical genetic analyses focused on transcriptomics, while also developing
a novel strategy for genetic manipulation of patient-derived epithelial cells. There are four major
biomedical genomics focus areas addressed by the research, namely fine mapping of loci influencing
inflammatory bowel disease, elucidation of the cell and molecular function of causal genes, understanding
how polymorphism influences pathology, and translating quantitative genetic discoveries into clinical
outcomes. Specifically, integrative genomics expertise will be used to refine the credible intervals
responsible for complex association signals at individual loci, enhance transcriptional risk scores (TRS) that
have recently been shown to provide much greater prediction of disease and progression than genetic risk
scores, and explore the potential of in silico predicted transcriptome-wide association studies in the context
of IBD. These studies will utilize the IBDGC datasets through collaborative arrangements mediated by data
coordinating center. In addition, proof of principle for the use of lipid nanoparticles as an efficient and
specific delivery system for genome editing and/or pharmaceutical delivery to targeted cell types in gut-
derived organoids will be demonstrated. Single cell RNA-Seq will be used to partition variability in gut
epithelial gene expression in the half dozen most common organoid cell types into contributions of the
ethnicity, location of the biopsy, type of disease, and source laboratory. This data will serve as a foundation
for evaluating the effects of a half dozen gene knock-outs across cell types using the lipid nanoparticle
delivery system. All analyses and reagents will be made available to consortium members as expected for
collaborative IBDGC research.
项目摘要
在过去的十年里,NIDDK IBDGC(炎症性肠病遗传学联合会)
生成了非凡的数据集,以支持对发病、进展和治疗的遗传分析
对克罗恩病和溃疡性结肠炎的反应。这一辅助项目将补充正在进行的IBDGC
通过提供专注于转录组学的并行统计遗传分析进行的研究,同时也在开发
患者来源的上皮细胞的基因操作的新策略。有四个主要的
研究涉及的生物医学基因组学重点领域,即影响基因座的精细定位
炎症性肠病,阐明致病基因的细胞和分子功能,了解
多态如何影响病理学,以及如何将定量的基因发现转化为临床
结果。具体地说,将使用综合基因组学专业知识来细化可信区间
负责单个基因座上的复杂关联信号,提高转录风险分数(TRS),
最近被证明比遗传风险对疾病和进展的预测要好得多
分数,并探索在电子预测转录组全关联研究中的潜力
IBD的症状。这些研究将通过以数据为中介的协作安排来利用IBDGC数据集
协调中心。此外,使用脂质纳米粒作为一种有效和
用于基因组编辑和/或药物递送到肠道中目标细胞类型的特定递送系统-
我们将展示衍生的有机化合物。单细胞RNA-Seq将用于划分肠道中的可变性
上皮基因表达在六种最常见的器质性细胞类型中的贡献
种族、活检地点、疾病类型和来源实验室。这些数据将作为基础
使用脂质纳米颗粒评估六种不同细胞类型的基因敲除的效果
传送系统。所有分析和试剂将按预期向财团成员提供
合作的IBDGC研究。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Canalization of the Polygenic Risk for Common Diseases and Traits in the UK Biobank Cohort.
- DOI:10.1093/molbev/msac053
- 发表时间:2022-04-11
- 期刊:
- 影响因子:10.7
- 作者:Nagpal, Sini;Tandon, Raghav;Gibson, Greg
- 通讯作者:Gibson, Greg
Integrative polygenic analysis of the protective effects of fatty acid metabolism on disease as modified by obesity.
- DOI:10.3389/fnut.2023.1308622
- 发表时间:2023
- 期刊:
- 影响因子:5
- 作者:Astore, Courtney;Gibson, Greg
- 通讯作者:Gibson, Greg
Perspectives on rigor and reproducibility in single cell genomics.
- DOI:10.1371/journal.pgen.1010210
- 发表时间:2022-05
- 期刊:
- 影响因子:4.5
- 作者:
- 通讯作者:
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GREGORY C GIBSON其他文献
GREGORY C GIBSON的其他文献
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{{ truncateString('GREGORY C GIBSON', 18)}}的其他基金
New computational, transcriptional, and genome editing approaches to the biology of inflammatory bowel disease
研究炎症性肠病生物学的新计算、转录和基因组编辑方法
- 批准号:
9976502 - 财政年份:2018
- 资助金额:
$ 17.27万 - 项目类别:
eQTL mega-analysis for functional assessment of multi-enhancer gene regulation
用于多增强子基因调控功能评估的 eQTL 大分析
- 批准号:
9330894 - 财政年份:2016
- 资助金额:
$ 17.27万 - 项目类别:
eQTL mega-analysis for functional assessment of multi-enhancer gene regulation
用于多增强子基因调控功能评估的 eQTL 大分析
- 批准号:
9072104 - 财政年份:2016
- 资助金额:
$ 17.27万 - 项目类别:
A Computational Biology and Predictive Health Genomics Training Program at GT
GT 的计算生物学和预测健康基因组学培训项目
- 批准号:
9285807 - 财政年份:2014
- 资助金额:
$ 17.27万 - 项目类别:
A Computational Biology and Predictive Health Genomics Training Program at GT
GT 的计算生物学和预测健康基因组学培训项目
- 批准号:
8473373 - 财政年份:2014
- 资助金额:
$ 17.27万 - 项目类别:
QUANTITATIVE GENETIC ANALYSIS OF SIGNAL TRANSDUCTION
信号转导的定量遗传分析
- 批准号:
6630485 - 财政年份:2000
- 资助金额:
$ 17.27万 - 项目类别:
QUANTITATIVE GENETIC ANALYSIS OF SIGNAL TRANSDUCTION
信号转导的定量遗传分析
- 批准号:
6525921 - 财政年份:2000
- 资助金额:
$ 17.27万 - 项目类别:
Quantitative Genetic Analysis of Signal Transduction
信号转导的定量遗传分析
- 批准号:
6924864 - 财政年份:2000
- 资助金额:
$ 17.27万 - 项目类别:
Quantitative Genetic Analysis of Signal Transduction
信号转导的定量遗传分析
- 批准号:
7025823 - 财政年份:2000
- 资助金额:
$ 17.27万 - 项目类别:
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