Cell fate choices by Tbx1 in forming the mammalian heart
Tbx1 在形成哺乳动物心脏过程中的细胞命运选择
基本信息
- 批准号:10615781
- 负责人:
- 金额:$ 60.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-20 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:22q11.23-DimensionalAPLN geneATAC-seqAffectAllelesAnteriorAortaBindingBinding ProteinsBinding SitesBiological ProcessCardiacCardiac MyocytesCell Differentiation processCell modelCellsChIP-seqChromatinChromosome MappingChromosomesDataData SetDefectDiGeorge SyndromeEctopic ExpressionEmbryoEmbryonic DevelopmentFaceGene Expression ProfileGeneral PopulationGenesGeneticGenetic TranscriptionHeartHeart AbnormalitiesHuman GeneticsImmunofluorescence ImmunologicIndividualLungMammalsMesenchymeMesodermMesoderm CellMolecularMusMuscleMuscle FibersMutant Strains MiceMutationNeckNeonatalPathway interactionsPatientsPenetrancePersistent Truncus ArteriosusPharyngeal ApparatusPhenocopyPopulationPopulation DynamicsPopulation SizesProcessProteinsRegulatory ElementRisk FactorsShprintzen syndromeSyndromeTestingTimeTissuescardiogenesiscell behaviorcell typeconditional mutantcongenital heart disorderembryo tissueexperimental studyfunctional genomicsgastrulationgene networkinterestmouse modelmutantprecursor cellprogenitorprogramsreceptorsingle-cell RNA sequencingspatiotemporalstem cellstranscription factortranscriptomics
项目摘要
TBX1 encodes a T-box transcription factor required for cardiac development. This gene maps to
the chromosome 22q11.2 region that is deleted in patients with DiGeorge syndrome/velo-cardio-
facial syndrome or 22q11.2 deletion syndrome (22q11.2DS). Approximately 60% of 22q11.2DS
patients have congenital heart disease that mostly affects the cardiac outflow tract. A subset of
individuals with a mutation of the TBX1 gene but not a deletion has been identified and they
partially phenocopy patients with 22q11.2DS. Inactivation of one allele of Tbx1 in mice results in
mild defects, but inactivation of both alleles results in neonatal lethality with a persistent truncus
arteriosus, in which the aorta and pulmonary trunk fail to separate. This defect also occurs in 5-
10% of 22q11.2DS patients with congenital heart disease. To understand the function of Tbx1 in
mammals, we performed single cell RNA-sequencing (scRNA-seq) of cardiopharyngeal
mesoderm progenitor cells within the pharyngeal apparatus. We discovered a multilineage
progenitor (MLP) population that expresses genes important for forming the cardiac outflow tract
as well as branchiomeric muscles of the face and neck. The MLP population expands at the
expense of more differentiated populations when Tbx1 is inactivated in the cardiopharyngeal
mesoderm. Our main hypothesis is that Tbx1 is required in the MLP population for progression
towards more differentiated states needed for cardiac development. We propose three specific
aims to test this hypothesis. In the first aim, we will perform additional scRNA-seq experiments
and analyze the complete dataset to understand how the progression of MLP cells are altered in
Tbx1 conditional and global mutant mouse embryos. In Aim 2, we will determine where the MLP
cells are localized in the embryo. Preliminary data suggests that these cells are localized to the
nascent mesenchyme of the elongating pharyngeal apparatus. We will also inactivate Tbx1
specifically within the MLP cells to determine its particular functions. In Aim 3, we will turn to
functional genomic studies and will identify open and accessible chromatin for which harbors
TBX1 protein binding sites using ATAC-seq and ChIP-seq from embryo tissue. Preliminary data
suggests that we are able to identify direct transcriptional target genes. By these three aims, we
will understand the molecular functions of TBX1 in the progression of progenitor cells to more
differentiated states to build the cardiac outflow tract.
Tbx1编码心脏发育所需的T-box转录因子。这个基因映射到
DiGeorge综合征/心动过速患者染色体22q11.2区缺失
面部综合征或22q11.2缺失综合征(22q11.2DS)。约60%的22q11.2DS
患者患有先天性心脏病,主要影响心脏流出道。的子集
已经鉴定出具有TBX1基因突变但没有缺失的个体,他们
部分表型患者有22q11.2DS。小鼠中TBX1的一个等位基因失活导致
轻度缺陷,但两个等位基因都失活会导致持续性干新生儿死亡
动脉硬化症,其中的主动脉和肺动脉干不能分离。这一缺陷也发生在5-
22q11.2DS合并先天性心脏病的占10%。要了解TBX1在
,我们进行了心咽单细胞rna测序(scrna-seq)。
咽器官内的中胚层祖细胞。我们发现了一个多血统
表达对形成心脏流出道重要的基因的祖细胞(MLP)群体
以及面部和颈部的臂肌。MLP的人口在
当TBX1在心咽部失活时,更多分化的群体的代价
中胚层。我们的主要假设是Tbx1在MLP人群中是疾病进展所必需的
心脏发育所需的更多分化状态。我们提出了三个具体的
旨在检验这一假说。在第一个目标中,我们将进行额外的scrna-seq实验。
并分析完整的数据集,以了解MLP细胞的进展是如何在
TBX1条件突变和全局突变小鼠胚胎。在目标2中,我们将确定MLP的位置
细胞定位于胚胎中。初步数据显示,这些细胞定位于
伸长的咽器的新生间充质。我们还将停用TBX1
特别是在MLP细胞内,以确定其特定功能。在目标3中,我们将转向
功能基因组研究,并将确定开放的和可获得的染色质
利用ATAC-SEQ和CHIP-SEQ从胚胎组织中获得了Tbx1蛋白结合位点。初步数据
这表明我们能够识别直接转录的靶基因。通过这三个目标,我们
将了解TBX1在祖细胞向更多
分化状态以建立心脏流出道。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Polycomb complexes redundantly maintain epidermal stem cell identity during development.
- DOI:10.1101/gad.345363.120
- 发表时间:2021-03-01
- 期刊:
- 影响因子:10.5
- 作者:Cohen I;Bar C;Liu H;Valdes VJ;Zhao D;Galbo PM Jr;Silva JM;Koseki H;Zheng D;Ezhkova E
- 通讯作者:Ezhkova E
Polycomb repressive complex 2 in adult hair follicle stem cells is dispensable for hair regeneration.
- DOI:10.1371/journal.pgen.1009948
- 发表时间:2021-12
- 期刊:
- 影响因子:4.5
- 作者:Flora P;Li MY;Galbo PM Jr;Astorkia M;Zheng D;Ezhkova E
- 通讯作者:Ezhkova E
Robust integration of multiple single-cell RNA sequencing datasets using a single reference space.
- DOI:10.1038/s41587-021-00859-x
- 发表时间:2021-07
- 期刊:
- 影响因子:46.9
- 作者:Liu Y;Wang T;Zhou B;Zheng D
- 通讯作者:Zheng D
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
BERNICE E MORROW其他文献
BERNICE E MORROW的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('BERNICE E MORROW', 18)}}的其他基金
Molecular pathogenesis of congenital heart disease mediated by neural crest and second heart field cells
神经嵴和第二心野细胞介导先天性心脏病的分子发病机制
- 批准号:
10621288 - 财政年份:2022
- 资助金额:
$ 60.56万 - 项目类别:
Genetic modifiers of congenital heart disease in 22q11.2 deletion syndrome
22q11.2缺失综合征先天性心脏病的遗传修饰
- 批准号:
10373375 - 财政年份:2022
- 资助金额:
$ 60.56万 - 项目类别:
Genetic modifiers of congenital heart disease in 22q11.2 deletion syndrome
22q11.2缺失综合征先天性心脏病的遗传修饰
- 批准号:
10553279 - 财政年份:2022
- 资助金额:
$ 60.56万 - 项目类别:
Molecular pathogenesis of congenital heart disease mediated by neural crest and second heart field cells
神经嵴和第二心野细胞介导先天性心脏病的分子发病机制
- 批准号:
10435713 - 财政年份:2022
- 资助金额:
$ 60.56万 - 项目类别:
Molecular and cellular mechanisms in cardiac outflow tract formation and defects
心脏流出道形成和缺陷的分子和细胞机制
- 批准号:
10289982 - 财政年份:2021
- 资助金额:
$ 60.56万 - 项目类别:
Molecular and cellular mechanisms in cardiac outflow tract formation and defects
心脏流出道形成和缺陷的分子和细胞机制
- 批准号:
10471433 - 财政年份:2021
- 资助金额:
$ 60.56万 - 项目类别:
Cell fate choices by Tbx1 in forming the mammalian heart
Tbx1 在形成哺乳动物心脏过程中的细胞命运选择
- 批准号:
10242828 - 财政年份:2020
- 资助金额:
$ 60.56万 - 项目类别:
相似海外基金
REU Site: Design, Create, and Innovate 3-Dimensional User Interfaces to Improve Human Sensory and Motor Performance in Virtual Environments (HUMANS MOVE)
REU 网站:设计、创建和创新 3 维用户界面,以提高虚拟环境中的人类感官和运动表现 (HUMANS MOVE)
- 批准号:
2349771 - 财政年份:2024
- 资助金额:
$ 60.56万 - 项目类别:
Standard Grant
CAREER: Atomic-level understanding of stability and transition kinetics of 3-dimensional interfaces under irradiation
职业:对辐照下 3 维界面的稳定性和转变动力学的原子水平理解
- 批准号:
2340085 - 财政年份:2024
- 资助金额:
$ 60.56万 - 项目类别:
Continuing Grant
Artificial fabrication of 3-dimensional noncollinear magnetic order and magnetization manipulation by spin torque
三维非共线磁序的人工制造和自旋转矩磁化操纵
- 批准号:
23H00232 - 财政年份:2023
- 资助金额:
$ 60.56万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
Understanding of 3-dimensional seismic behavior of RC frame high-speed railway/highway viaducts using FE analysis
使用有限元分析了解 RC 框架高速铁路/公路高架桥的 3 维抗震性能
- 批准号:
23H01489 - 财政年份:2023
- 资助金额:
$ 60.56万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Modernization of 3-dimensional printing capabilities at the Aquatic Germplasm and Genetic Resource Center
水产种质和遗传资源中心 3 维打印能力的现代化
- 批准号:
10736961 - 财政年份:2023
- 资助金额:
$ 60.56万 - 项目类别:
The 3-dimensional nest of the honey bee: organization, development, and impact on colony function
蜜蜂的 3 维巢穴:组织、发育及其对蜂群功能的影响
- 批准号:
2216835 - 财政年份:2023
- 资助金额:
$ 60.56万 - 项目类别:
Standard Grant
Research on high-density 3-dimensional polymer optical waveguide device for photonics-electronics convergence
光电子融合高密度三维聚合物光波导器件研究
- 批准号:
23H01882 - 财政年份:2023
- 资助金额:
$ 60.56万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Scaff-Net: 3 Dimensional multiphoton polymerisation printed scaffolds for medium throughput recording from stem cell derived human cortical networks.
Scaff-Net:3 维多光子聚合打印支架,用于从干细胞衍生的人类皮质网络进行中等通量记录。
- 批准号:
EP/X018385/1 - 财政年份:2023
- 资助金额:
$ 60.56万 - 项目类别:
Research Grant
3-dimensional prompt gamma imaging for online proton beam dose verification
用于在线质子束剂量验证的 3 维瞬发伽马成像
- 批准号:
10635210 - 财政年份:2023
- 资助金额:
$ 60.56万 - 项目类别:
Equipment: MRI: Track 1 Acquisition of a 3-Dimensional Nanolithography Instrument
设备:MRI:轨道 1 获取 3 维纳米光刻仪器
- 批准号:
2320636 - 财政年份:2023
- 资助金额:
$ 60.56万 - 项目类别:
Standard Grant