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
项目摘要/摘要
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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科研奖励(0)
会议论文
Decoding and reprogramming T cells through synthetic biology for cancer immunotherapy
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批准号:10568704
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资助金额:$77.15万
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财政年份:2022
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依托单位:
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批准号:10576380
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项目类别:
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资助金额:$39.3万
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财政年份:2022
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负责人:Alexander Marson
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依托单位:
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批准号:10576392
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项目类别:
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资助金额:$47.16万
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财政年份:2022
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负责人:Alexander Marson
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依托单位:
Project 3: CRISPR Genome Editing to Understand and Correct STAT3 GOF Immune Dysregulation
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批准号:10328103
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项目类别:
-
资助金额:$47.25万
-
财政年份:2022
-
负责人:Alexander Marson
-
依托单位:
Project 3
-
批准号:10666677
-
项目类别:
-
资助金额:$98.3万
-
财政年份:2022
-
负责人:Alexander Marson
-
依托单位:
Core B: Human Genetics and Genomics Core
-
批准号:10328100
-
项目类别:
-
资助金额:$17.39万
-
财政年份:2022
-
负责人:Alexander Marson
-
依托单位:
Editing to Create and Correct Gene Variants
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批准号:10462633
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项目类别:
-
资助金额:$44.54万
-
财政年份:2020
-
负责人:Alexander Marson
-
依托单位:
Inherited T cell defects: Diagnosis, Mechanisms and Treatments
-
批准号:10728891
-
项目类别:
-
资助金额:$8.71万
-
财政年份:2020
-
负责人:Alexander Marson
-
依托单位:
Editing to Create and Correct Gene Variants
-
批准号:10256630
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项目类别:
-
资助金额:$41.98万
-
财政年份:2020
-
负责人:Alexander Marson
-
依托单位:
Inherited T cell defects: Diagnosis, Mechanisms and Treatments
-
批准号:10462628
-
项目类别:
-
资助金额:$221.8万
-
财政年份:2020
-
负责人:Alexander Marson
-
依托单位:
Inherited T cell defects: Diagnosis, Mechanisms and Treatments
-
批准号:10705413
-
项目类别:
-
资助金额:$10.55万
-
财政年份:2020
-
负责人:Alexander Marson
-
依托单位:
Administrative Core
-
批准号:10024568
-
项目类别:
-
资助金额:$7.68万
-
财政年份:2020
-
负责人:Alexander Marson
-
依托单位:
Administrative Core
-
批准号:10666736
-
项目类别:
-
资助金额:$1.28万
-
财政年份:2020
-
负责人:Alexander Marson
-
依托单位:
Inherited T cell defects: Diagnosis, Mechanisms and Treatments
-
批准号:10024567
-
项目类别:
-
资助金额:$221.8万
-
财政年份:2020
-
负责人:Alexander Marson
-
依托单位:
Administrative Core
-
批准号:10705414
-
项目类别:
-
资助金额:$10.55万
-
财政年份:2020
-
负责人:Alexander Marson
-
依托单位:
Inherited T cell defects: Diagnosis, Mechanisms and Treatments
-
批准号:10666735
-
项目类别:
-
资助金额:$1.28万
-
财政年份:2020
-
负责人:Alexander Marson
-
依托单位:
Administrative Core
-
批准号:10462629
-
项目类别:
-
资助金额:$16.24万
-
财政年份:2020
-
负责人:Alexander Marson
-
依托单位:
Inherited T cell defects: Diagnosis, Mechanisms and Treatments
-
批准号:10256624
-
项目类别:
-
资助金额:$221.8万
-
财政年份:2020
-
负责人:Alexander Marson
-
依托单位:
Administrative Core
-
批准号:10256625
-
项目类别:
-
资助金额:$16.11万
-
财政年份:2020
-
负责人:Alexander Marson
-
依托单位:
海外基金