Comparative genetics of cardiac chamber formation

心室形成的比较遗传学

• 批准号: 6988540
• 负责人: DEBORAH YELON
• 金额: $ 16.72万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-05 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6988540
• 关键词: animal genetic material tag; antisense nucleic acid; cardiogenesis; clinical research; developmental genetics; endoderm; gene expression; gene expression profiling; in situ hybridization; laboratory mouse; myocardium; oligonucleotides; transcription factor; vertebrate embryology; zebrafish

DESCRIPTION (provided by applicant): The identification of genetic pathways controlling cardiac chamber formation is likely to illuminate the molecular mechanisms responsible for many cardiac structural birth defects. The cardiac homeodomain transcription factor gene Nkx2-5 is known to play a key role in cardiac development: Nkx2-5 is essential for normal chamber formation in mice, and mutations in human Nkx2-5 underlie familial cases of congenital heart disease. Despite the clear importance of Nkx2-5 in the cardiac regulatory hierarchy, the downstream components of the Nkx2-5 pathway and their contributions to cardiac chamber formation are not well understood. The PIs hypothesize that the essential effector genes for cardiac chamber formation are evolutionarily conserved components of the Nkx2-5 pathway. To test this hypothesis, they propose a two-year exploratory project that combines the expertise of the Yelon and Harvey laboratories for a comparative genetic analysis of Nkx2-5 function in zebrafish and mouse. Specifically, they will begin by characterizing the molecular anatomy of the zebrafish heart as a foundation for comparative analysis. Applying this knowledge, they will compare the loss-of-function phenotypes for the Nkx2-5 gene family in zebrafish and mouse. Then, taking advantage of advances in both mouse and zebrafish genomics, they will combine microarray analysis and comparative gene expression studies to identify genes downstream of Nkx2-5 in both species. Finally, with attention focused on conserved pathway components, they will utilize zebrafish reverse genetics to test their roles during cardiac chamber formation. Together, the proposed experiments will reveal conserved roles and components of the Nkx2-5 pathway. Furthermore, by capitalizing on the complementary advantages of two model organisms, the PIs will develop a new approach for functional annotation of cardiac gene expression profiles.

描述（由申请人提供）：控制心脏腔形成的遗传途径的鉴定可能会阐明导致许多心脏结构出生缺陷的分子机制。心脏同源域转录因子基因NKX2-5在心脏发展中起关键作用： NKX2-5对于小鼠的正常腔室形成至关重要，人类NKX2-5的突变是先天性心脏病的家族病例。尽管NKX2-5在心脏调节层次结构中显然重要，但NKX2-5途径的下游成分及其对心脏腔室形成的贡献尚不很好。 PI假设心脏腔形成的基本效应基因是NKX2-5途径的进化保守成分。为了检验这一假设，他们提出了一个为期两年的探索项目，该项目结合了Yelon和Harvey Laboratories的专业知识，以对斑马鱼和小鼠的NKX2-5功能进行比较遗传分析。具体而言，它们将首先表征斑马鱼心的分子解剖结构作为比较分析的基础。应用这些知识，他们将比较斑马鱼和小鼠中NKX2-5基因家族的功能丧失表型。然后，利用小鼠和斑马鱼基因组学的进步，它们将结合微阵列分析和比较基因表达研究，以鉴定这两个物种中NKX2-5下游的基因。最后，由于注意力集中在保守的途径成分上，他们将利用斑马鱼反向遗传学在心脏腔形成期间测试其作用。共同提出的实验将揭示NKX2-5途径的保守作用和成分。此外，通过利用两个模型生物的互补优势，PIS将开发出一种新方法来对心脏基因表达谱的功能注释。