Using Chromatin Architecture to Develop of Therapeutic Pipeline for Juvenile Arthritis
Using Chromatin Architecture to Develop of Therapeutic Pipeline for Juvenile Arthritis
批准号:
10241246
负责人:
JAMES N JARVIS
金额:
$17.02万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-08-21 至 2023-07-31
关键词:
AffectArchitectureAttenuatedAutoimmune DiseasesBiologyBudgetsCellsChildChromatinChromatin LoopChronic Childhood ArthritisChronic DiseaseClinicalCoupledDNADataDevelopmentDiseaseDrug TargetingElementsEnhancersEnzymesEpigenetic ProcessGene ExpressionGene TargetingGene-ModifiedGenesGeneticGenetic Enhancer ElementGenetic RiskGenomeGenomic SegmentGenomicsGoalsGuide RNAHaplotypesIL2RA geneIndustryInterest GroupIntronsLeadLymphoid CellMethodsMutationPathologicPatient CareProteinsQuantitative Reverse Transcriptase PCRRiskStructureTechniquesTherapeuticTimeTissuesTranslatingUntranslated RNAWorkbaseepigenome editingepigenomicsgenetic informationgenetic variantgenome sequencinggenome wide association studyimprovednew therapeutic targetnucleasepromoterrisk variantscale uptargeted treatmenttherapeutic targetwhole genome
中文摘要
摘要
在这个项目中,我们的目标是朝着确定青少年癌症治疗的新靶点迈出重要的一步。
特发性关节炎(JIA)。为了做到这一点,我们将使用基因组产生的遗传信息-
广泛关联研究(GWAS)和遗传精细作图研究。这些研究表明,
JIA的遗传风险存在于增强子功能高度富集的基因组区域,这一特征
JIA与几乎所有其他自身免疫性疾病相同。这项工作的基本前提是,
识别改变增强子功能的遗传风险变体,然后识别其表达
当增强子功能改变时,水平改变,我们将确定有前途的新的治疗靶点。
在这个概念验证项目中,我们将重点关注IL 2 RA,这是JIA和多种其他疾病的重要风险位点。
自身免疫性疾病我们先前已经表明,IL 2 RA基因座含有一个内含子增强子,
我们最初在儿童全基因组测序中发现的遗传变异削弱了功能
多关节型JIA我们的目标是确定这些遗传变异的靶基因,即,的基因
其表达水平在内含子增强子的功能减弱时改变。为了实现这一
为了达到这个目的,我们依赖于这样一个事实,即虽然增强子可能并不总是调节最近的基因,但它们通常调节
同一染色质环或拓扑相关结构域(topologically associated domain,简写为UTR)内的基因。我们将使用RNA引导的
用与表观基因组编辑酶偶联的失活核酸酶进行表观基因组编辑,Krüppel相关
盒(KRAB)阻遏物(dCAS-KRAB)。然后,我们将使用传统的rtPCR方法来确定哪些是
12个基因被整合到含有IL 2 RA增强子的cDNA中,显示出表达的变化。
当增强子减弱时水平。
如果成功的话,我们将建立使用更广泛的染色质作为概念验证的效用
该架构结合了JIA风险单体型和RNA指导的表观基因组编辑作为一种策略,
确定JIA的治疗靶点。我们期望这项工作的完成将很快导致一个更大的项目
目的是鉴定JIA风险基因座内遗传改变增强子的所有靶基因。此外,委员会认为,
成功完成还将导致与主要行业领导者的伙伴关系的发展,
将这些发现应用于临床。
!
英文摘要
Abstract
In this project, we aim to take an important step toward identifying novel targets of therapy in juvenile
idiopathic arthritis (JIA). To do this, we will use genetic information that has been generated from genome-
wide association studies (GWAS) and genetic fine mapping studies. These studies have shown that much of
the genetic risk for JIA lies within genomic regions that are highly enriched for enhancer function, a feature that
JIA shares with almost every other autoimmune disease. The underlying premise of this work is that, by
identifying genetic risk variants that alter enhancer function, and then identifying the genes whose expression
levels change when enhancer function is altered, we will identify promising new therapeutic targets.
In this proof-of-concept project, we will focus on IL2RA, an important risk locus for JIA and multiple other
autoimmune diseases. We have previously shown that the IL2RA locus contains an intronic enhancer whose
function is attenuated by genetic variants that we initially identified on whole genome sequencing of children
with the polyarticular form of JIA. We aim to identify the target genes of these genetic variants, i.e., the genes
whose expression levels are altered when function of the intronic enhancer is attenuated. To accomplish this
aim, we rely on the fact that, while enhancers may not always regulate the nearest gene, they typically regulate
genes within the same chromatin loop or topologically associated domain (TAD). We will use RNA-guided
epigenome editing with a deactivated nuclease coupled to an epigenome editing enzyme, Krüppel associated
box (KRAB) repressor (dCAS-KRAB). We will then use conventional rtPCR approaches to identify which of the
12 genes that are incorporated within the TAD that contains the IL2RA enhancer show changes in expression
level when that enhancer is attenuated.
If successful, we will have established as proof-of-concept the utility of using the broader chromatin
architecture that incorporates the JIA risk haplotypes and RNA-guided epigenome editing as a strategy for
identify therapeutic targets in JIA. We expect that completion of this work will lead quickly to a larger project
aimed at identifying all the target genes of genetically altered enhancers within the JIA risk loci. Furthermore,
successful completion will also lead to the development of partnerships with key industry leaders to rapidly
translate these findings to the clinical setting.
!
期刊论文(0)
专著(0)
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会议论文
Epigenetic Mechanisms That Drive Genetic Risk in Juvenile Arthritis
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批准号:10364303
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项目类别:
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资助金额:$65.31万
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财政年份:2022
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负责人:JAMES N JARVIS
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依托单位:
Epigenetic Mechanisms That Drive Genetic Risk in Juvenile Arthritis
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批准号:10710032
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资助金额:$63.11万
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财政年份:2022
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负责人:JAMES N JARVIS
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依托单位:
3D Chromatin Studies in Pediatric B Cells To Study the Genetics of Autoimmunity
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批准号:10351558
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项目类别:
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资助金额:$7.98万
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财政年份:2021
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负责人:JAMES N JARVIS
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依托单位:
3D Chromatin Studies in Pediatric B Cells To Study the Genetics of Autoimmunity
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批准号:10514624
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项目类别:
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资助金额:$7.98万
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财政年份:2021
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负责人:JAMES N JARVIS
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依托单位:
Using Chromatin Architecture to Develop of Therapeutic Pipeline for Juvenile Arthritis
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批准号:9927736
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项目类别:
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资助金额:$21.05万
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财政年份:2020
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负责人:JAMES N JARVIS
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依托单位:
Identifying Causal Variants in Juvenile Arthritis Using a Massively Parallel Reporter Assay
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批准号:9767028
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项目类别:
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资助金额:$17.55万
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财政年份:2018
-
负责人:JAMES N JARVIS
-
依托单位:
Trophoblasts and Inflammation: An Epigenetic Approach
-
批准号:8693451
-
项目类别:
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资助金额:$23.85万
-
财政年份:2014
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负责人:JAMES N JARVIS
-
依托单位:
Trophoblasts and Inflammation: An Epigenetic Approach
-
批准号:8840286
-
项目类别:
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资助金额:$19.43万
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财政年份:2014
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负责人:JAMES N JARVIS
-
依托单位:
Microarray-Based Biomarkers in Juvenile Idiopathic Arthritis
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批准号:8546146
-
项目类别:
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资助金额:$47.44万
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财政年份:2011
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负责人:JAMES N JARVIS
-
依托单位:
Microarray-Based Biomarkers in Juvenile Idiopathic Arthritis
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批准号:8892088
-
项目类别:
-
资助金额:$48.55万
-
财政年份:2011
-
负责人:JAMES N JARVIS
-
依托单位:
Microarray-Based Biomarkers in Juvenile Idiopathic Arthritis
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批准号:8475183
-
项目类别:
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资助金额:$13.63万
-
财政年份:2011
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负责人:JAMES N JARVIS
-
依托单位:
Microarray-Based Biomarkers in Juvenile Idiopathic Arthritis
-
批准号:8640883
-
项目类别:
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资助金额:$51.8万
-
财政年份:2011
-
负责人:JAMES N JARVIS
-
依托单位:
Microarray-Based Biomarkers in Juvenile Idiopathic Arthritis
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批准号:8220723
-
项目类别:
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资助金额:$46.76万
-
财政年份:2011
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负责人:JAMES N JARVIS
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依托单位:
Microarray-Based Biomarkers in Juvenile Idiopathic Arthritis
-
批准号:8683720
-
项目类别:
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资助金额:$2.84万
-
财政年份:2011
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负责人:JAMES N JARVIS
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依托单位:
Microarray-Based Biomarkers in Juvenile Idiopathic Arthritis
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批准号:8057424
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项目类别:
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资助金额:$46.03万
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财政年份:2011
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负责人:JAMES N JARVIS
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依托单位:
Dynamics of Therapeutic Response Within the TREAT Trial
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批准号:8138725
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项目类别:
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资助金额:$0.99万
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财政年份:2010
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负责人:JAMES N JARVIS
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依托单位:
Dynamics of Therapeutic Response Within the TREAT Trial
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批准号:7747572
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项目类别:
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资助金额:$31.7万
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财政年份:2009
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负责人:JAMES N JARVIS
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依托单位:
Dynamics of Therapeutic Response Within the TREAT Trial
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批准号:7929530
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项目类别:
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资助金额:$68.37万
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财政年份:2009
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负责人:JAMES N JARVIS
-
依托单位:
MICROARRAYS IN TREATED JUVENILE RHEUMATOID ARTHRITIS
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批准号:7203322
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项目类别:
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资助金额:$0.07万
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财政年份:2005
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负责人:JAMES N JARVIS
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依托单位:
IDENTIFYING NOVEL IMMUNE REGULATORS IN PLACENTAL TROPHOBLASTS
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批准号:7203343
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项目类别:
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资助金额:$0.17万
-
财政年份:2005
-
负责人:JAMES N JARVIS
-
依托单位:
海外基金