Nkx2-5 and congenital heart defects in Xenopus

Nkx2-5 与爪蟾先天性心脏缺陷

• 批准号: 6992703
• 负责人: DANIEL L. WEEKS
• 金额: $ 28.81万
• 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/6992703
• 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）：先天性心脏缺陷使近1％的新生儿受苦，并且在多达10％的死亡婴儿中发现。心脏病的遗传原因包括NKX2-5转录因子中的突变。目前，关于NKX2-5的知识是通过检查有机体的发展，使人类中的人相似的结构可以学到多少。 NKX2-5是果蝇基因Tinman的同源物。 Tinman之所以获得其名字，是因为没有这个基因的苍蝇未能形成热量，例如绿野仙踪中的Tinman。只有单个正常副本的NKX2-5副本的人具有先天性心脏缺陷形式的心房间隔缺陷，而传导问题与法洛的共鸣缺陷和四个学科。到目前为止，NKX2-5似乎是哺乳动物中心脏发育的单一相关基因，但是在青蛙Xenopus laevis中，有三个相关基因，XNKX2-3、2-5、2-10都作为心形形式。我们提出的研究旨在测试这些基因中的每个基因在心脏发育中的独特和重叠功能。我们将使用基于反义寡核苷酸的方法来降低特定基因表达，而mRNA添加实验来确定哪种基因产物可以挽救其他基因的耗竭。我们还将研究本研究的新转座子，“睡美人”的使用，用于生成转基因胚胎。我们建议在Xenopus中，已经分裂了人类NKX2-5基因的多个功能，因此提供了一个独特的机会来更好地理解这种医学重要的基因的功能。