New Mouse Models of Microphthamia

描述（由申请人提供）：先天性眼睛缺陷是比较常见的，经常损害视力或导致失明。小眼症是一种严重的先天性眼睛缺陷，在其他问题中，眼睛不能长到正常大小。由于小眼症发生在胎儿发育早期，对其主要原因或人眼发育中发生的变化知之甚少。在过去的几年里，有几个基因已经被证实与人类的小眼症有关。其中一种Chx10引起非综合征性双侧小眼，患有这种疾病的儿童天生失明。已经确定了三种错义突变，但携带这些突变的人类眼部发育的进展尚不清楚。这些研究的主要目标是表征由Chx10突变引起的发育表型，这些突变是人类的基础。我们的方法是使用转基因敲入技术在小鼠中产生三种人类突变中的两种，并表征所产生的表型。表型将在胚胎、新生儿和成年小鼠中通过组织学方法确定，包括原位杂交和免疫组织化学。这些研究的完成可以为人类小眼症相关的发育变化提供重要的见解，并进一步解决Chx10在眼睛形成，特别是视网膜发育中的作用。先天性眼畸形是相对常见的先天缺陷，可导致视力受损或失明。小眼症是一种严重的畸形，目前还没有有效的矫正治疗方法。Chx10基因的三个突变导致人类小眼症。我们已经建立了携带两种人类突变的小鼠模型，这项资助的一个重要目标是表征眼睛发育过程中发生的缺陷，以便更好地了解人类小眼症的病因。

DESCRIPTION (provided by applicant): Congenital eye defects are relatively common and oftentimes impair vision or cause blindness. Microphthalmia is a severe congenital eye defect in which the eye fails to grow to its normal size, among other problems. Because the onset of microphthalmia occurs early in fetal development, very little is known about its primary causes or the changes that occur in human eye development. In the past few years, several genes have been conclusively linked to microphthalmia in humans. One of them, Chx10, causes non-syndromic, bilateral microphthalmia and children with this condition are born blind. Three missense mutations have been identified, but the progression of ocular development in humans with these mutations is not known. The primary goal of these studies is to characterize the developmental phenotypes caused by the mutations in Chx10 that are founding humans. Our approach is to produce two of the three human mutations in the mouse using transgenic knock-in technology and characterize the resulting phenotypes. Phenotypes will be determined in embryos, neonates, and adult mice by histological methods including in situ hybridization and immunohistochemistry. Completion of these studies could provide significant insight into the developmental changes associated with microphthalmia in humans and further resolve the role of Chx10 in eye formation, and in particular, retinal development. Congenital eye anomalies are relatively common birth defects that cause visual impairments or blindness. Microphthalmia, or small eye, is a severe anomaly for which there is no available corrective treatment. Three mutations in the Chx10 gene cause micropthalmia in humans. We have generated mouse models that carry two of the human mutations and an important goal of this grant is to characterize the defects that occur during eye development in order to better understand the etiology of human microphthalmia.