Analysis of Congenital Hydrocephalus Genes in Xenopus

项目摘要 先天性脑积水（CH），由于脑脊液导致脑室的病理性扩张 (CSF)累积是一种常见的出生缺陷，每1 000名新生儿中就有1人患有这种缺陷，死亡率和发病率都很高。 治疗选择仅限于手术，失败率为50%。缺乏治疗方法， 部分原因是对脑积水发病机制认识不全面。当前人类遗传学研究 在CH患者中鉴定了新的候选基因（SMARCC 1，TRIM 71，PTCH 1，SHH）。 神经干细胞的作用，其在脑积水发病机制中的作用是未知的。在这项工作中，我们将使用青蛙 爪蟾模型系统，以了解潜在的发病机制。我们最近的工作配对光学相干 断层扫描成像（OCT）和CRISPR/CAS9系统与青蛙爪蟾，以模拟人类先天性 脑积水我们证明，突变蝌蚪的OCT成像可以很容易地检测到人类的特征， 脑积水，包括导水管狭窄和脑室扩大。重要的是爪蟾作为一个模型系统， 可以快速评估CH候选基因，并区分沟通与非沟通的发病机制 机制等我们的中心假设是，由于不同的遗传背景，CH的发病机制将是不同的。 脑室形态、CSF流动网络和神经祖细胞命运存在离散差异， 对治疗的重要意义。总的来说，我们的目标是阐明脑积水的机制 发病机制，以确定新的目标，医疗管理的选择。

Project Summary Congenital Hydrocephalus (CH), the pathological expansion of the cerebral ventricles due to cerebrospinal fluid (CSF) accumulation, is a common birth defect affecting 1 in every 1000 births, with high mortality and morbidity. Treatment options are limited to surgery, which has a 50% failure rate. The lack of treatment modalities is, in part, due to our incomplete understanding of hydrocephalus pathogenesis. Current human genetics studies identified novel candidate genes (SMARCC1, TRIM71, PTCH1, SHH) in patients with CH. Despite their known roles in neural stem cells, their role in hydrocephalus pathogenesis is unknown. In this work, we will use the frog Xenopus model system to understand the underlying pathogenesis. Our recent work paired optical coherence tomography imaging (OCT) and CRISPR/CAS9 system with the frog Xenopus to model human congenital hydrocephalus. We demonstrated that OCT imaging of mutant tadpoles could readily detect hallmarks of human hydrocephalus, including aqueductal stenosis and ventriculomegaly. Importantly Xenopus, as a model system, can rapidly evaluate CH candidate genes and distinguish communicating vs. non-communicating pathogenesis mechanisms. Our central hypothesis is that the pathogenesis of CH due to different genetic backgrounds will be discretely different for ventricular morphology, CSF flow network, and neural progenitor cell fate, which can have important implications for treatment. Overall, our goal is to shed light on the mechanism of hydrocephalus pathogenesis to identify novel targets for medical management options.