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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：
10442889
负责人：
Vittorio Sebastiano
金额：
$ 39.35万
依托单位：
STANFORD UNIVERSITY
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：
https://reporter.nih.gov/project-details/10442889
关键词：
22q11 22q11.2 ATAC-seq Affect Anatomy Animal Model Arteries Binding Biocompatible Materials Biology Branchial arch structure CRISPR interference Cell Therapy Cell model Cells ChIP-seq Chromatin Chromosome 22 Congenital Heart Defects DNA Data Development DiGeorge Syndrome Disease Dissection Embryonic Development Endoderm Endoderm Cell Endothelium Enhancers Ensure Epigenetic Process Face Gene Expression Generations Genes Genetic Genetic Screening Genetic Transcription Heart Histones Human In Vitro Intervention Knowledge Maps Mesoderm Methods Modeling Molecular Molecular Genetics Mus Muscle Mutation Neural Crest Cell Nucleic Acid Regulatory Sequences Parathyroid gland Pathway interactions Patients Pattern Pharmacology Pharyngeal Apparatus Pharyngeal structure Phase Phenotype Physiological Play Population Qi Regulation Role Signal Transduction Structure Syndrome System Testing Thymus Gland Tissues Validation Work base cell type clinical phenotype craniofacial developmental disease dosage epigenetic regulation experimental study gene regulatory network genetic variant genome sequencing human embryonic stem cell human model human tissue in vitro Model in vivo insight microdeletion multidisciplinary new technology novel pharyngeal patterning prevent reconstruction response stem cell biology tool transcription factor transcriptome transcriptome sequencing whole 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