Molecular Cytogenetics of Congenital Heart Malformation

先天性心脏畸形的分子细胞遗传学

• 批准号: 7231425
• 负责人: ANTONIO BALDINI
• 金额: $ 34.49万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-05 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231425
• 关键词: Address; Alleles; Animals; Aorta; Arteries; Binding; Binding Sites; Boxing; Branchial arch structure; Candidate Disease Gene; Cardiovascular system; Cells; Chimera organism; Collection; Congenital Abnormality; Congenital Heart Defects; Data; Defect; Development; DiGeorge Syndrome; Double Outlet Right Ventricle; Elements; Embryo; Endoderm; Enhancers; Fibroblast Growth Factor; Gene Expression; Genes; Genetic; Genetic Structures; Growth; Heart; Human; Mediating; Mediator of activation protein; Mesoderm; Modeling; Molecular Cytogenetics; Morphogenesis; Mus; Mutation; Pathogenesis; Patients; Pharmaceutical Preparations; Pharyngeal Apparatus; Pharyngeal pouch; Pharyngeal structure; Phenotype; Play; Publishing; Role; Severities; Signal Pathway; Signal Transduction; Site; Source; System; Testing; Tetralogy of Fallot; Time; Tissues; Transgenic Organisms; aortic arch; base; forkhead protein; in vivo; mutant; promoter; research study

DESCRIPTION (provided by applicant): The broad aim of this project is to dissect genetically the role of Tbx1 during pharyngeal and cardiovascular development. Tbx1 is required for the development of the pharyngeal arches and pouches and is a key candidate gene for DiGeorge Syndrome. Developmental defects of the embryonic pharyngeal apparatus are the basis of many human birth defects, including different types of congenital heart abnormalities. This project is driven by a model in which Tbx1 has an early, cell-autonomous function in pharyngeal segmentation and a later, cell non-autonomous function in the growth and remodeling of the pharyngeal arch arteries. The early function is proposed to be dependent upon genetic control of Tbx1 in the endoderm, and the late function is proposed to be dependent upon genetic interactions between Tbx1 and the fibroblast growth factor (FGF) signaling pathway. To address this model, 4 specific aims are proposed: 1) To distinguish the late from the early roles of Tbx1 by inactivating the gene in a time-controlled manner. 2) To establish the role of an endoderm enhancer of Tbx1 during pharyngeal morphogenesis, by modifying the enhancer in the endogenous gene. 3) To understand the role of the FGF signaling in the pathogenesis of the Tbx1 mutant phenotype. This will be achieved by a) testing the ability of FGF activity to rescue the Tbx1 mutant phenotype b) disrupting T-box binding sites from the Fgf8 and Fgf10 genes, and c) testing the ability of Tbx1 to activate Fgf genes ectopically. 4) To understand the role of Tbx1 in the alignment of the outflow tract using tissue-specific deletion. It is proposed that this role is also mediated by the FGF signaling. Published and preliminary data support the proposed model, and the collection of Tbx1 mutant alleles already generated and that will be generated with this project, should provide a unique opportunity to dissect the role of Tbx1 in cardiovascular and pharyngeal development.

描述（由申请人提供）：本项目的主要目的是剖析Tbx1基因在咽部和心血管发育中的作用。Tbx1是咽弓和咽袋发育所必需的，是diggeorge综合征的关键候选基因。胚胎咽器的发育缺陷是许多人类出生缺陷的基础，包括不同类型的先天性心脏异常。这个项目是由一个模型驱动的，在这个模型中，Tbx1在咽部分割中具有早期的细胞自主功能，而在咽部弓动脉的生长和重塑中具有后期的细胞非自主功能。早期功能被认为依赖于内胚层中Tbx1的遗传控制，晚期功能被认为依赖于Tbx1与成纤维细胞生长因子（FGF）信号通路之间的遗传相互作用。为了解决这一模型，我们提出了4个具体目标：1)通过时间控制的方式使Tbx1基因失活来区分其晚期和早期作用。2)通过修饰内源性基因中的增强子，确定Tbx1内胚层增强子在咽部形态发生中的作用。3)了解FGF信号在Tbx1突变表型发病机制中的作用。这将通过a)测试FGF活性拯救Tbx1突变表型的能力；b)破坏Fgf8和Fgf10基因的T-box结合位点；c)测试Tbx1异位激活FGF基因的能力来实现。4)通过组织特异性缺失了解Tbx1在流出道排列中的作用。这一作用也可能是由FGF信号传导介导的。

项目成果

Fgf8 expression in the Tbx1 domain causes skeletal abnormalities and modifies the aortic arch but not the outflow tract phenotype of Tbx1 mutants.

• DOI: 10.1016/j.ydbio.2006.03.044
• 发表时间: 2006-07
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: F. Vitelli;Zhen Zhang;Tuong Huynh;Angela Sobotka;Annalisa Mupo;A. Baldini

A genetic link between Tbx1 and fibroblast growth factor signaling.

Tbx1 和成纤维细胞生长因子信号传导之间的遗传联系。

• DOI: 10.1242/dev.129.19.4605
• 发表时间: 2002
• 期刊: Development (Cambridge, England)
• 作者: Vitelli,Francesca;Taddei,Ilaria;Morishima,Masae;Meyers,ErikN;Lindsay,ElizabethA;Baldini,Antonio
• 通讯作者: Baldini,Antonio

A mouse gene (Dgcr6) related to the Drosophila gonadal gene is expressed in early embryogenesis and is the homolog of a human gene deleted in DiGeorge syndrome.

与果蝇性腺基因相关的小鼠基因（Dgcr6）在早期胚胎发生中表达，并且是迪乔治综合征中删除的人类基因的同源物。

• DOI: 10.1159/000134736
• 发表时间: 1997
• 期刊: Cytogenetics and cell genetics
• 作者: Lindsay,EA;Baldini,A
• 通讯作者: Baldini,A

Ece1 and Tbx1 define distinct pathways to aortic arch morphogenesis.

Ece1 和 Tbx1 定义了主动脉弓形态发生的不同途径。

• DOI: 10.1002/dvdy.10358
• 发表时间: 2003
• 期刊: Developmental dynamics : an official publication of the American Association of Anatomists.
• 作者: Morishima,Masae;Yanagisawa,Hiromi;Yanagisawa,Masashi;Baldini,Antonio
• 通讯作者: Baldini,Antonio

Structure and expression of the human ubiquitin fusion-degradation gene (UFD1L).

人类泛素融合降解基因（UFD1L）的结构和表达。

• DOI: 10.1016/s0167-4781(97)00211-x
• 发表时间: 1998
• 期刊: Biochimica et biophysica acta
• 作者: Novelli,G;Mari,A;Amati,F;Colosimo,A;Sangiuolo,F;Bengala,M;Conti,E;Ratti,A;Bordoni,R;Pizzuti,A;Baldini,A;Crinelli,R;Pandolfi,F;Magnani,M;Dallapiccola,B
• 通讯作者: Dallapiccola,B