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

这个项目试图确定心脏发育中心腔形成的发育原理，以及这种发育原理如何在遗传性心脏缺陷中变得异常。我们研究的基因Nkx2-5编码一种与DNA结合的蛋白质，并调节形成脑室的遗传程序的表达。我们认为Nkx2-5是一种执行调节器？控制其他调控因子的时间和空间表达，从而控制肌肉分化和形态发育(形态发生)所需的一系列基因的表达。最近发现，人类Nkx2-5基因的一个副本的突变与房间隔缺陷或心脏Ohole有关，这是一种有时严重的心脏结构遗传性缺陷。该基因的两个副本都发生突变的小鼠胚胎在脑室形成方面存在严重得多的缺陷，与生命不相容。这些研究旨在扩大我们对心脏心腔形成的遗传调控的理解。我们将首先使用基因打靶技术制作人类疾病的小鼠模型，这使得我们能够对这种动物的单个基因进行精确的改变。其次，我们将把新技术应用于心脏，使我们能够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签和激光来测量细胞身份，已经在免疫学领域产生了很大影响，但可以适应心脏。我们将用它来分离和鉴定胚胎中形成心脏的宝贵的早期细胞。正是在这些细胞中，人类和老鼠的突变产生了最初的影响。我们的研究对于了解和筛选人类遗传性心脏异常，以及了解心脏形成的一般原理，可能揭示干预心脏病的有价值的方法都具有相关性。

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.