Nkx2-5 and congenital heart defects in Xenopus

Nkx2-5 与爪蟾先天性心脏缺陷

• 批准号: 6719707
• 负责人: DANIEL L. WEEKS
• 金额: $ 29.5万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6719707
• 关键词: DNA binding protein; Xenopus; antisense nucleic acid; cardiogenesis; congenital heart disorder; developmental genetics; gene expression; immunocytochemistry; in situ hybridization; oligonucleotides; protein structure function; transcription factor

DESCRIPTION (provided by applicant): Congenital heart defects afflict nearly 1% of all newborns, and are found in as many as 10% of stillborn babies. Among the genetic causes of heart disease are mutations in the Nkx2-5 transcription factor. What is currently known about Nkx2-5 is an example of how much can be learned by examining development in organism that make analogous structures to those in human. Nkx2-5 is a homologue of the fruit fly gene, tinman. Tinman received its name because flies without this gene fail to form a heat, like the tinman in the Wizard of OZ. Humans with only a single normal copy of Nkx2-5 have congenital heart defects ranging form atrial septal defects, and conduction problems to conotruncal defects and tetrology of Fallot. So far, Nkx2-5 seems to be the single relevant tinman related gene for cardiac development in mammals, but in the frog Xenopus laevis, there are three related genes, Xnkx2-3, 2-5 and 2-10 all present as the heart forms. We propose studies aimed at testing each of these genes for unique and overlapping function in heart development. We will be using antisense oligonucleotide based approaches to reduce specific gene expression, and mRNA addition experiments to establish which gene product can rescue depletion of the others. We will also examine the use of a new transposon, Sleeping Beauty, for generation of transgenic embryos for this study. We propose that in Xenopus the multiple functions of the Nkx2-5 gene in humans have been split up, and thus provide a unique opportunity to better understand the function of this medically important gene.

描述（由申请人提供）：先天性心脏缺陷困扰着近1%的新生儿，并在多达10%的死产婴儿中发现。心脏病的遗传原因之一是Nkx 2 -5转录因子的突变。目前对Nkx 2 -5的了解是一个例子，说明通过研究生物体的发育可以了解到多少，这些生物体的结构与人类相似。nkx 2 -5是果蝇基因tinman的同源物。锡人之所以得名，是因为没有这种基因的苍蝇无法形成热量，就像绿野仙踪中的锡人一样。只有一个正常拷贝的Nkx 2 -5的人类有先天性心脏缺陷，从房间隔缺损，传导问题到圆锥动脉干缺损和法洛四联症。迄今为止，Nkx 2 -5似乎是哺乳动物心脏发育的唯一相关基因，但在非洲爪蟾中，有三个相关基因，Xnkx 2 -3，2-5和2-10都以心脏形式存在。我们提出了旨在测试这些基因中的每一个在心脏发育中的独特和重叠功能的研究。我们将使用基于反义寡核苷酸的方法来减少特定的基因表达，并通过mRNA添加实验来确定哪种基因产物可以拯救其他基因的缺失。我们还将研究使用一种新的转座子，睡美人，为这项研究产生转基因胚胎。我们提出，在非洲爪蟾的Nkx 2 -5基因在人类中的多种功能已经分裂，从而提供了一个独特的机会，以更好地了解这个医学上重要的基因的功能。