Role of Homeobox Gene Nkx2-5 in Heart Development and Congenital Heart Disease

同源盒基因 Nkx2-5 在心脏发育和先天性心脏病中的作用

• 批准号: nhmrc : 109002
• 负责人: Prof Richard Harvey
• 金额: $ 15.16万
• 依托单位: Victor Chang Cardiac Research Institute
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2000
• 资助国家: 澳大利亚
• 起止时间: 2000-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/role-homeobox-gene-heart-disease/81905
• 关键词: Role; Homeobox; Gene; Nkx2; Heart

This project seeks to define the developmental principles underlying chamber formation in the developing heart and how this becomes abnormal in inherited heart defects. The gene we study, Nkx2-5, encodes a protein which binds to DNA and regulates the expression of the genetic program for formation of the ventricles, the pumping chambers of the heart. We believe that Nkx2-5 is an Oexecutive regulator? of this program, controlling the timing and spatial expression of other regulators that then control expression of a host of genes required for muscle differentiation and the development of form (morphogenesis). Mutations in one copy of the human Nkx2-5 gene have recently been discovered to be associated with atrial septal defect, or Ohole in the heartO, a sometimes serious inherited defect in heart structure. Mouse embryos with a mutation in both copies of the gene have a much more serious defect in ventricle formation that is incompatible with life. The studies are designed to extend our understanding of the genetic regulation of chamber formation in the heart. We will firstly make a mouse model of the human disease using gene targeting technology, which allows us to make precise alteration in single genes in this animal. Secondly, we will apply new technology to the heart that will let us visualise molecular and cellular events at higher resolution. This technology, which uses fluorescent tags on cells and a laser to measure cell identity, has been used to great affect in the field of immunology, but can be adapted to the heart. We will use it to isolate and characterise the precious early cells that give rise to the heart in the embryo. It is in these cells that the human and mouse mutations have their first effects. Our studies have relevance to understanding and screening for human inherited heart abnormalities, and for understanding the general principles of heart formation that may reveal valuable ways to intervene in heart disease.

该项目旨在定义发育中心脏心室形成的发育原则，以及这在遗传性心脏缺陷中如何变得异常。我们研究的基因Nkx 2 -5编码一种蛋白质，该蛋白质与DNA结合并调节形成心室（心脏的泵室）的遗传程序的表达。我们认为Nkx 2 -5是一个执行调节器？这一程序，控制其他调节器的时间和空间表达，然后控制肌肉分化和形式（形态发生）的发展所需的基因表达的主机。最近发现人类Nkx 2 -5基因的一个拷贝的突变与心房间隔缺损或心脏O孔有关，这是一种有时严重的心脏结构遗传缺陷。在两个基因拷贝中都有突变的小鼠胚胎在心室形成方面有更严重的缺陷，这与生命不相容。这些研究旨在扩大我们对心脏腔室形成的遗传调控的理解。我们将首先使用基因靶向技术制作人类疾病的小鼠模型，这使我们能够在这种动物中精确改变单个基因。其次，我们将把新技术应用于心脏，让我们以更高的分辨率可视化分子和细胞事件。这项技术使用细胞上的荧光标记和激光来测量细胞身份，已经在免疫学领域产生了很大的影响，但也可以适用于心脏。我们将用它来分离和培养胚胎中产生心脏的宝贵的早期细胞。正是在这些细胞中，人类和小鼠的突变产生了最初的影响。我们的研究与了解和筛查人类遗传性心脏异常有关，并了解心脏形成的一般原则，这些原则可能揭示干预心脏病的有价值的方法。