Dissecting the Molecular Role of TBX1 in the Context of Human Pharyngeal Endoderm Development
解析 TBX1 在人咽内胚层发育中的分子作用
基本信息
- 批准号:10615234
- 负责人:
- 金额:$ 39.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-01 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:22q11.2ATAC-seqAffectAnatomyAnimal ModelArteriesBindingBiocompatible MaterialsBiologyBranchial arch structureCRISPR interferenceCell TherapyCell modelCellsChIP-seqChromatinChromosome 22Congenital Heart DefectsDNADataDevelopmentDiGeorge SyndromeDiseaseDissectionEmbryonic DevelopmentEndodermEndoderm CellEndotheliumEnhancersEnsureEpigenetic ProcessFaceGene DeletionGene ExpressionGenerationsGenesGeneticGenetic ScreeningGenetic TranscriptionHeartHeterozygoteHistonesHumanIn VitroInterventionKnowledgeMapsMesodermMethodsModelingMolecularMusMuscleMutationNeural Crest CellNucleic Acid Regulatory SequencesParathyroid glandPathway interactionsPatientsPatternPharyngeal ApparatusPharyngeal structurePhasePhenotypePhysiologicalPlayPopulationQiRegulationRoleSignal TransductionStructureSyndromeSystemTestingThymus GlandTissuesValidationWorkcell typeclinical phenotypecraniofacialdevelopmental diseasedosageepigenetic regulationexperimental studygene regulatory networkgenetic variantgenome sequencinghuman embryonic stem cellhuman modelhuman tissuein vitro Modelin vivoinsightmicrodeletionmultidisciplinarynew technologynovelpharmacologicpharyngeal patterningpreventreconstructionresponsestem cell biologytooltranscription factortranscriptometranscriptome sequencingwhole genome
项目摘要
PROJECT SUMMARY
22q11.2 Deletion Syndrome (22q11.2DS), the most common of the microdeletion syndromes, is caused by
hemizygous loss of 0.7-3 Mb of DNA on chromosome 22 and results in a constellation of clinical phenotypes.
The core phenotype originates from disrupted development of the pharyngeal apparatus. Particularly affected
are the second heart field-dependent heart structures, great vessels, parathyroids, thymus, and lower
craniofacial and face muscles. Although approximately 50 genes may be deleted, it is the haploinsufficiency of
the transcription factor TBX1 that recapitulates most of the critical phenotype associated with 22q11.2DS.
Genetic and developmental mouse studies have established that TBX1 is critical for typical development of the
pharyngeal endoderm, a transient anatomical structure necessary for development of the thymus, parathyroids,
and 4th pharyngeal arch arteries. Despite this central role, very little is known regarding the molecular
mechanisms by which TBX1 functions in the pharyngeal endoderm. While a handful of studies have attempted
to study the role of TBX1 in human cells, the cell types they have been conducted in are not representative of
the appropriate developmental stage where and when TBX1 plays its critical role. To date, an effort to integrate
all the critical genes into a pharyngeal endoderm or 4th pharyngeal arch arteries network has not been attempted,
particularly in human cells.
This R01 leverages recent development of an in vitro model which faithfully mimics the formation and progression
of human pharyngeal endoderm, thereby providing an unprecedented opportunity to tease out the functions of
TBX1 in its physiological context. Specifically, this model will be used to identify the transcriptional targets and
partners of TBX1 (Aim1), investigate the role of TBX1 as epigenetic regulator of the human pharyngeal endoderm
(Aim2), and mechanistically investigate newly discovered putative regulatory regions of the TBX1 locus (Aim3).
The overarching hypothesis is that TBX1 is at the center of a Gene Regulatory Network critical for both the
formation and maturation of the pharyngeal endoderm and the morpho-patterning of the surrounding mesoderm
and neural crest cells.
The proposed work is expected to identify the molecular mechanism at the basis of TBX1 haploinsufficiency and
identify pathways which could be rescued through pharmacological intervention. Dissection of the epigenetic
and molecular machinery responsible for pharyngeal endoderm formation will be instrumental in informing the
generation of cell therapies for 22q11.2DS.
项目总结
项目成果
期刊论文数量(0)
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Vittorio Sebastiano其他文献
Vittorio Sebastiano的其他文献
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{{ truncateString('Vittorio Sebastiano', 18)}}的其他基金
Dissecting the Molecular Role of TBX1 in the Context of Human Pharyngeal Endoderm Development
解析 TBX1 在人咽内胚层发育中的分子作用
- 批准号:
10442889 - 财政年份:2022
- 资助金额:
$ 39.35万 - 项目类别:
Single Step Strategy for the Therapeutic Reprogramming in Epidermolysis Bullosa Patients
大疱性表皮松解症患者治疗性重编程的一步策略
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9475196 - 财政年份:2017
- 资助金额:
$ 39.35万 - 项目类别:
Single Step Strategy for the Therapeutic Reprogramming in Epidermolysis Bullosa Patients
大疱性表皮松解症患者治疗重编程的一步策略
- 批准号:
9317254 - 财政年份:2017
- 资助金额:
$ 39.35万 - 项目类别:
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