Prevention of cleft palate: the critical role of p63 and IRF6 signalling

在婴儿的发育过程中，两个截然不同的部分融合在一起，形成了上颚(口腔顶部)。目前，我们还不完全清楚是什么控制了这些事件，但我们确实知道，当上颌的两半未能融合时，就会导致常见的、令人痛苦的出生缺陷腭裂。患有腭裂的患者在进食和说话方面存在困难，这些困难可以通过长期的手术、牙科治疗和语言治疗在一定程度上得到纠正；因此，我们必须更多地了解基因在正常发育过程中是如何协同工作的，以及这些基因在腭裂中是如何受到影响的。这个项目的目的是研究两个基因，命名为p63和irf6，在味觉发育过程中如何共同发挥作用。到目前为止，我们已经发现P63开启了IRF6的功能，而这反过来又会导致P63的水平在上颚的两半融合之前下降。在我们的初步研究中，我们将确定当p63在发育中的小鼠的腭部保持人为高水平时，是否会导致腭裂。随后，通过发现由p63和IRF6控制的靶基因，我们将获得更完整的味觉发育方式的图景。短期内，这项研究将帮助我们了解腭部正常发育的基础过程，以及这些过程是如何在腭裂中被破坏的。从长远来看，这些信息可能有助于我们为受这种令人痛苦的疾病影响的患者及其家人提供更好的基因诊断和咨询。

The palate (the roof of the mouth) develops from two distinct parts that fuse together during development of the baby. Currently, we do not completely understand what controls these events, but we do know that the common and distressing birth defect cleft palate results when fusion of the two halves of the palate fails to occur. Patients with cleft palate experience difficulties with eating and speaking, which can be corrected to some degree by long-term surgery, dental treatment, and speech therapy; it is therefore essential that we have more information on how genes work together during normal development and how these are affected in cleft palate. The aim of this project is to study the way in which two genes, designated p63 and IRF6, function together during development of the palate. So far, we have discovered that p63 switches on the function of IRF6 and that this, in turn, causes the levels of p63 to drop just before fusion of the two halves of the palate. In our initial studies, we will determine whether or not cleft palate results when p63 is maintained at an artificially high level in the palate of developing mice. Subsequently, we will obtain a more complete picture of the ways in which the palate develops by discovering the target genes controlled by p63 and IRF6. In the short-term, this research will help us to understand the processes that underlie normal development of the palate and how these are disrupted in cleft palate. In the longer term, this information may help us to provide improved genetic diagnosis and counselling to patients and their families who are affected by this distressing condition.