Understanding the role that cellular hypoxia plays in normal heart development

先天性心脏缺陷（CHD）是最常见的出生缺陷类型，每1000例活产婴儿中有6例存在先天性心脏缺陷，10%的死胎存在先天性心脏缺陷。除了在儿童时期死亡的危险外，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CHD的遗传原因。我们正在研究两种基因，即HIF 1a和CITED 2，我们已经有证据表明它们在胚胎内正常形成心脏方面非常重要。因为心脏是胚胎中形成的第一个器官（在前三个月），我们不能用人类来研究这个过程。相反，我们有两个品系的小鼠，它们在整个胚胎中特别缺乏HIF 1a或CITED 2基因。这两种小鼠都有严重的心脏缺陷，类似于人类中发现的某些类型的CHD。然而，去除这些基因中的任何一个也会导致其他组织的严重缺陷，使我们的研究复杂化。为了克服这个问题，我们将使用一种稍微不同的技术，专门在胚胎的整个发育心脏中去除任何一种基因，而在胚胎的其余部分保留正常基因。因此，我们将首次能够单独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是CHD的一种特殊亚型。如果这是真的，在未来，我们希望能够证明这些基因中的任何一个突变都会导致特定类型的人类CHD。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.