Analysis of Congenital Hydrocephalus Genes in Xenopus

非洲爪蟾先天性脑积水基因分析

基本信息

批准号：
10626955
负责人：
ENGIN DENIZ
金额：
$ 46.58万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626955
关键词：
3-Dimensional Affect Animal Model Binding Biological Models Birth Brain CRISPR/Cas technology Candidate Disease Gene Cells Cerebral Ventricles Cerebrospinal Fluid Childhood Chromatin Remodeling Factor Cilia Circulation Clustered Regularly Interspaced Short Palindromic Repeats Communication Congenital Abnormality Congenital Hydrocephalus Defect Development Disease Embryo Failure Fluids and Secretions Future Genes Genetic Genetic study Genomics Goals Human Human Genetics Hydrocephalus Image Immunohistochemistry In Situ Hybridization Infant Lead Legal patent Liquid substance Medical Membrane Modality Morbidity - disease rate Morphology Mutation Obstruction Obstructive Hydrocephalus Operative Surgical Procedures Optical Coherence Tomography Outcome Pathogenesis Pathologic Pathway interactions Patients Pattern Phenotype Process Proliferating Protein Secretion Rana Regulation Role SHH gene SMARCA4 gene SMARCC1 gene Signal Pathway Signal Transduction Stenosis System Tadpoles Testing Thinness Time Ventricular Visualization Work Xenopus absorption cell motility cerebrospinal fluid flow cilium biogenesis cilium motility design human model imaging modality imaging platform improved mortality mutant nerve stem cell neural neural patterning neurodevelopment neuroepithelium neurogenesis novel novel strategies receptor stem cell biology therapy design transcriptomic profiling ubiquitin-protein ligase ventricular system

项目摘要

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.

项目概要先天性脑积水（CH），脑脊液引起的脑室病理性扩张（脑脊液）积聚是一种常见的出生缺陷，每 1000 名新生儿中就有 1 人患有脑脊液积聚，死亡率和发病率很高。治疗选择仅限于手术，其失败率为 50%。缺乏治疗方法是部分原因是我们对脑积水发病机制的了解不完全。当前的人类遗传学研究在 CH 患者中鉴定出新的候选基因（SMARCC1、TRIM71、PTCH1、SHH）。尽管他们已知尽管其在神经干细胞中的作用，但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蟾模型系统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 系统与青蛙爪蟾一起模拟人类先天性脑积水。我们证明突变蝌蚪的 OCT 成像可以轻松检测人类的特征脑积水，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发病机制机制。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。心室形态、脑脊液血流网络和神经祖细胞命运存在离散差异，这可能有对治疗有重要意义。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医疗管理方案的新目标。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reply to Pisan et al.: Pathogenicity of inherited TRAF7 mutations in congenital heart disease.

回复Pisan等人：遗传性TRAF7突变在先天性心脏病中的致病性。

DOI：
10.1073/pnas.2319578121
发表时间：
2024
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Mishra-Gorur,Ketu;Barak,Tanyeri;Kaulen,LeonD;Henegariu,Octavian;Jin,ShengChih;Aguilera,StephanieMarie;Yalbir,Ezgi;Goles,Gizem;Nishimura,Sayoko;Miyagishima,Danielle;Djenoune,Lydia;Altinok,Selin;Rai,DevendraK;Viviano,Stephen;
通讯作者：

Xenopus Tadpole Craniocardiac Imaging Using Optical Coherence Tomography.