New Mouse Models of Microphthamia

描述(申请人提供)：先天性眼睛缺陷比较常见，通常会损害视力或导致失明。小眼球是一种严重的先天性眼睛缺陷，眼睛无法生长到正常大小，以及其他问题。由于小眼炎发生在胎儿发育的早期，人们对其主要原因或人类眼睛发育过程中发生的变化知之甚少。在过去的几年里，有几个基因被确定与人类的小眼球有关。其中一种是Chx10，会导致非综合征的双眼小眼炎，患有这种疾病的儿童出生时就会失明。已经确定了三个错义突变，但带有这些突变的人类眼睛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，CHX10是人类的创立者。我们的方法是使用转基因敲入技术在小鼠身上产生三种人类突变中的两种，并对产生的表型进行表征。将通过包括原位杂交和免疫组织化学在内的组织学方法来确定胚胎、新生儿和成年小鼠的表型。这些研究的完成可以为人类与小眼球相关的发育变化提供重要的洞察力，并进一步解决Chx10在眼睛形成，特别是视网膜发育中的作用。先天性眼畸形是一种相对常见的先天缺陷，会导致视力障碍或失明。小眼球，或小眼睛，是一种严重的异常，没有可用的矫正治疗。Chx10基因的三个突变会导致人类的小眼球。我们已经产生了携带两种人类突变的小鼠模型，这笔赠款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球的病因。

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.