Functional Molecular Investigation of Inflammatory Bowel Disease (IBD) Risk Variants
Functional Molecular Investigation of Inflammatory Bowel Disease (IBD) Risk Variants
批准号:
10374675
负责人:
Alexander Marson
金额:
$18.9万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-03-18 至 2022-05-31
关键词:
AffectAmino AcidsAutoimmune DiseasesAutophagocytosisBacteriaBiochemicalBiologicalBiological MarkersCell physiologyCellsCellular StressCellular Stress ResponseChronic DiseaseClustered Regularly Interspaced Short Palindromic RepeatsCodeColitisCollaborationsComplexCouplesCrohn&aposs diseaseDNADataDevelopmentDiagnosisDiagnostic testsDiseaseDisease ProgressionDisease modelElectroporationElementsEnhancersEnsureEnvironmental Risk FactorEpigenetic ProcessEpithelialEtiologyFoundationsFunctional disorderFutureGene Expression RegulationGenesGeneticGenetic DiseasesGenetic VariationGenetic studyGenomeGenomicsGoalsHumanHuman GeneticsIL2RA geneImmuneImmune responseImmunologic SurveillanceImpairmentInflammatoryInflammatory Bowel DiseasesIntestinesInvestigationLearningMapsModelingMolecularMusMutationOpen Reading FramesOrganoidsPathogenicityPathologyPathway interactionsPatientsPhenotypeRegulator GenesRegulatory ElementRegulatory T-LymphocyteRestRiskRoleSiteStimulusSusceptibility GeneT-LymphocyteT-Lymphocyte SubsetsTestingTissuesUntranslated RNAVariantadaptive immune responsebasecausal variantcell typecellular pathologydisorder controldisorder riskdrug discoveryfallsgenetic architecturegenetic manipulationgenome editinggenome wide association studygenomic locushuman population studyin vivoin vivo evaluationinflammatory disease of the intestineinsightintestinal epitheliumintestinal homeostasismouse modelmultidisciplinarynew therapeutic targetnovel diagnosticsprogramsregeneration following injuryregenerativeresponserisk varianttargeted treatmenttissue regenerationtreatment responsezygote
中文摘要
项目总结/摘要
炎症性肠病(IBD)是一种以间歇性炎症为特征的慢性疾病,
肠道炎症发作和肠上皮屏障破坏。的
IBD遗传学联盟深入研究了这种复杂疾病的遗传结构。
IBD风险变异的分子机制对了解疾病至关重要
病原学和确定新的药物靶点。人类遗传学有潜力提供一个公正的观点
致病机制的研究IBD已经成为密集遗传学的主题,
研究,包括全基因组关联研究(GWAS),发现了数十种风险
的位点然而,对这些风险位点的机械理解一直是一个挑战,因为大量的
大多数福尔斯落在基因之外,在基因组的非编码区。相比
基因组的蛋白质编码区,我们了解氨基酸密码,我们仍然不知道
有一个清晰的框架来理解非编码基因组变异如何改变细胞功能,
有助于疾病。为了了解整个基因组中的DNA变异如何影响细胞
由于非编码途径和IBD的贡献,我们现在需要更深入地了解非编码途径的功能,
基因组元素在特定的细胞类型,驱动病理。
我们提出了在原代人T细胞、人T细胞和人T细胞中靶向的基于CRISPR的基因组扰动。
肠类器官(HIO)和IBD病理学的体内鼠模型来表征
关键的顺式调节元件和受IBD影响的功能途径
风险变量。原代免疫细胞、HIO和鼠模型中的基因组扰动将
确定由这些关键非编码元件调控的靶基因,
IBD风险变异损害基因的细胞类型或刺激特异性条件
调控我们将评估人类基因突变所涉及的位点的非编码变异
遗传学改变了静息状态下炎性和调节性T细胞的基因调节程序,
状态和对刺激的反应。此外,我们还将研究
增殖、上皮屏障和肠功能障碍的特异性遗传位点
完整性、自噬、细胞应激反应和再生能力
HIOs。了解因果性非编码IBD风险变体如何破坏人类关键基因程序
细胞具有加速靶向治疗方法发展的潜力。
英文摘要
PROJECT SUMMARY/ ABSTRACT
Inflammatory bowel disease (IBD) is a chronic disease characterized by intermittent
episodes of intestinal inflammation and disruption of the intestinal epithelial barrier. The
IBD Genetics Consortium has intensively studied the genetic architecture of this complex disease.
Assigning molecular mechanisms to IBD risk variants is critical to understanding disease
etiology and identify new drug targets. Human genetics has potential to provide an unbiased view
of the causative disease mechanisms. IBD already has been the subject of intensive genetic
investigations, including genome-wide association studies (GWAS) that have uncovered dozens of risk
loci. However, mechanistic understanding of these risk loci has been a challenge because the vast
majority falls outside of genes, in non-coding regions of the genome. In contrast to
protein-coding regions of the genome where we understand the amino acid code, we still do not
have a clear framework to understand how non-coding genome variants alter cell function and
contribute to disease. To learn how DNA variation throughout the genome affects cellular
pathways and contributes to IBD, we now need a deeper understanding of the function of non-coding
genome elements in the specific cell types that drive the pathology.
We propose targeted CRISPR-based genome perturbations in primary human T cells, human
intestinal organoids (HIOs) and in vivo murine models of IBD pathology to characterize
both critical cis-regulatory elements and functional pathways that are affected by IBD
risk variants. Genome perturbations in primary immune cells, HIOs and murine models will
identify target genes regulated by these critical non-coding elements and identify the
cell-type or stimulation-specific conditions where IBD risk variants impair gene
regulation. We will assess how non-coding variation at sites implicated by human
genetics alters gene regulatory programs in inflammatory and regulatory T cells in both resting
state and in response to stimuli. In addition, we will investigate the contribution of
specific genetic loci to intestinal dysfunction in proliferation, epithelial barrier
integrity, autophagy, cellular stress responses and regenerative ability using gene-edited
HIOs. Understanding how causal non-coding IBD risk variants disrupt key gene programs in human
cells has potential to accelerate development of targeted therapeutic approaches.
期刊论文(1)
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资助金额:$98.3万
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依托单位:
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资助金额:$17.39万
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Inherited T cell defects: Diagnosis, Mechanisms and Treatments
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依托单位:
Inherited T cell defects: Diagnosis, Mechanisms and Treatments
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资助金额:$221.8万
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负责人:Alexander Marson
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依托单位:
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资助金额:$10.55万
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负责人:Alexander Marson
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依托单位:
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海外基金