Understanding the role that cellular hypoxia plays in normal heart development

先天性心脏病(CHD)是最常见的出生缺陷类型，每1000名活产中就有6名，死产中有10%。除了在童年时死亡的危险外，这种心脏缺陷还会增加成年后患心脏病的风险。我们的研究项目涉及寻找冠心病的遗传原因。我们正在研究两个基因，称为HIF1a和CITED2，我们已经有证据表明，它们在允许心脏在胚胎中正常形成方面非常重要。因为心脏是第一个在胚胎中形成的器官(在怀孕的前三个月)，我们不能用人类来研究这一过程。相反，我们有两个品系的小鼠，它们在整个胚胎中都特别缺乏HIF1a或CITED2基因。这两种小鼠都有严重的心脏缺陷，类似于人类的某些类型的冠心病。然而，移除这些基因中的任何一个也会在其他组织中造成严重的缺陷，使我们的研究复杂化。为了解决这个问题，我们将使用一种略有不同的技术，专门在胚胎的整个发育心脏中移除这两个基因中的任何一个，同时将正常基因保留在胚胎的其余部分。因此，我们将第一次能够研究这些基因对心脏的影响。我们怀疑这些胚胎的心脏缺陷将属于特定的CHD亚型。如果这是真的，我们希望在未来能够证明这些基因中的任何一个的突变都会导致一种特定类型的人类冠心病。这将有助于对有冠心病病史的家庭进行基因筛查，协助遗传咨询，并促进治疗方法的发展。

Congenital heart defects (CHD) are the most common type of birth defects, being present in 6 out of every 1000 live births, and 10% of stillbirths. In addition to the danger of death during childhood, such heart defects also increase the risk of heart disease during adulthood. Our research project involves looking for the genetic causes of CHD. We are looking at two genes , called HIF1a and CITED2, for which we already have evidence that they are very important in allowing the heart to form normally within the embryo. Because the heart is the first organ to form in the embryo (during the first trimester), we cannot use humans to study this process. Instead we have two lines of mice which specifically lack either the HIF1a or CITED2 genes throughout the embryo. Both of these mouse lines have severe heart defects similar to some types of CHD seen in humans. However, removal of either of these genes also causes severe defects in other tissues, complicating our study. To overcome this problem, we will use a slightly different technique to remove either gene specifically in the entire developing heart of the embryo, while leaving the normal gene in the rest of the embryo. Thus we will be able for the first time to study the effects of these genes on the heart alone. We suspect that the defects in the hearts of such embryos will be of a particular sub-type of CHD. If this is true, in the future we hope to be able show that mutation of either of these genes will cause a specific type of human CHD. This will enable genetic screening of families with a history of CHD, assist in genetic counselling, and promote the development of therapies.