Molecular Cytogenetics of Congenital Heart Malformation

先天性心脏畸形的分子细胞遗传学

• 批准号: 6729503
• 负责人: ANTONIO BALDINI
• 金额: $ 37.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 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 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729503
• 关键词: cardiogenesis; congenital heart disorder; cytogenetics; developmental genetics; endoderm; fibroblast growth factor; gene mutation; genetic promoter element; genetically modified animals; laboratory mouse; mammalian embryology; transcription factor; velocardiofacial syndrome

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）：该项目的主要目的是从遗传学角度剖析Tbx1在咽和心血管发育过程中的作用。Tbx1是咽弓和咽囊发育所必需的，是DiGeorge综合征的关键候选基因。胚胎咽器官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。该项目由一个模型驱动，其中Tbx1在咽部分割中具有早期的细胞自主功能，在咽弓动脉的生长和重塑中具有晚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和成纤维细胞生长因子（FGF）信号通路之间的遗传相互作用。为了解决这个模型，提出了4个具体的目标：1）通过以时间控制的方式使基因失活来区分Tbx1的晚期和早期作用。2)通过修饰内源基因中的增强子，建立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Tbx 1突变表型的能力B）破坏Fgf 8和Fgf 10基因的T盒结合位点，和c）测试Tbx 1异位激活Fgf基因的能力来实现。4)了解Tbx1在使用组织特异性缺失的流出道对齐中的作用。有人提出，这种作用也是由FGF信号转导介导的。 已发表的和初步的数据支持所提出的模型，已经产生的和将产生的Tbx1突变等位基因的集合，应该提供一个独特的机会来剖析Tbx1在心血管和咽部发育中的作用。