Analysis of Congenital Hydrocephalus Genes in Xenopus

项目摘要 先天性脑积水，脑脊液引起的脑室病理性扩张 脑脊液(CSF)积聚是一种常见的出生缺陷，每1000名新生儿中就有一名出生，死亡率和发病率都很高。 治疗选择仅限于手术，失败率为50%。缺乏治疗方式是，在 第二部分，由于我们对脑积水发病机制的认识不够全面。现代人类遗传学研究 在CH患者中发现新的候选基因(SMARCC1、TRIM71、ptch1、SHH)。尽管他们已知 在神经干细胞中的作用，它们在脑积水发病机制中的作用尚不清楚。在这项工作中，我们将使用青蛙 非洲爪哇模型系统，以了解其潜在的发病机制。我们最近的工作是配对光学相干性 非洲爪蛙体层摄影术(OCT)和CRISPR/CAS9系统模拟人类先天性 脑积水。我们证明，突变蝌蚪的OCT成像可以很容易地检测出人类的特征 脑积水，包括导水管狭窄和脑室增大。重要的是，非洲爪哇作为一个模型系统， 可以快速评估CH候选基因并区分通信和非通信的发病机制 机械装置。我们的中心假设是由于不同的遗传背景导致的CH的发病机制将是 对于脑室形态、脑脊液流量网络和神经前体细胞命运的离散不同，可能有 对治疗有重要意义。总体而言，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，为医疗管理选择。

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.