Genetics and morphology of the middle ear ossicles in the developing mouse embryo

我对研究中耳小骨是如何发育的很感兴趣。这些小听骨的缺陷，如融合，是相当常见的，并导致听力问题。这些缺陷可以通过CT（计算机断层扫描）扫描看到，这可以评估患者是否适合进行矫正耳部手术。中耳由三个听骨组成，它们形成了一条连接鼓膜和内耳的链条。三个小听骨通过关节连接，关节可能畸形或缺失，导致中耳融合和听力丧失。在这些患者中，尚不清楚观察到的缺陷是如何产生的。这是由于缺乏关于这些关节在正常发育过程中形成的信息。这项研究试图通过研究中耳来纠正我们知识上的这一缺陷，首先在正常小鼠胚胎中，然后在突变小鼠胚胎中。小鼠中耳的发育已被证明与人类相似，因此使用小鼠模型获得的信息可与人类患者直接相关。我计划主要集中在前两个小骨和关节区域，因为这是最常发生缺陷的区域。我们首先想知道的是：和关节是如何形成的，和哪些基因参与了关节的形成，和关节的位置是如何决定的，和在正常的胚胎发育过程中，三个小骨是如何形成它们各自的特征（即它们彼此之间的差异）的。在确定了中耳的这个区域是如何正常形成的之后，我们将利用这些信息来调查有异常的情况。为此，我们将分析一种名为TCOF1的基因发生突变的小鼠胚胎。该基因有缺陷的患者会患上Treacher Collins综合征（TCS），几乎100%的病例都伴有中耳融合和听力丧失。这项工作应该提供一个清晰的图像，如何在胚胎学中看到中耳缺陷在TCS发生。最终，这些信息可以帮助TCS患者在讨论手术选择时做出更明智的决定。

I am interested in researching how the middle ear ossicles develop. Defects in these ossicles, such as fusion, are fairly common and lead to hearing problems. These defects can be seen by using CT (computed tomography) scans, which allow assessment of the patient s suitability for corrective ear surgery. The middle ear is composed of three ossicles that form a chain linking the ear drum with the inner ear. The three ossicles are connected by joints, which can be malformed or absent, resulting in fusion of the middle ear and hearing loss. In these patients it is unclear how the defects observed arose. This is due to a lack of information available with respect to formation of these joints during normal development.This research attempts to correct this deficit in our knowledge by investigating the middle ear, first in normal and then in mutant mouse embryos. Development of the mouse middle ear has been shown to be similar to that of humans and therefore information obtained from using mouse models can be directly related to human patients. I plan to concentrate mainly on the first two ossicles and joint region, as this is the region where defects most often occur. We would first like to know: sum How the joint forms sum What genes are involved in joint formation sum How is the position of the joint determined sum How do each of the three ossicles develop their individual specification (ie their difference from each other) during normal embryonic development.Having identifies how this region of the middle ear normally forms we will use this information to investigate cases where there is an abnormality. For this we will be analysing a mouse embryo that has a mutation in a gene called TCOF1. Patients with defects in this gene develop Treacher Collins syndrome (TCS) which is associated with a fused middle ear and hearing loss in almost 100% of cases. This work should give a clear picture of how the middle ear defects seen in TCS occur during embryology. Ultimately, such information may help patients with TCS by allowing for a more informed decision when the option for surgery is discussed.