Developmental Mechanisms of Human Meningomyelocele

人类脑膜脊髓膨出的发生机制

基本信息

批准号：
10300066
负责人：
JOSEPH G GLEESON
金额：
$ 139.06万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10300066
关键词：
Affect Alleles American Animal Model Attention Bioinformatics Brain Stem Candidate Disease Gene Child Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Communication Communities Congenital Abnormality Country Custom DNA DNA Methylation DNA Sequence Alteration DNA Sequencing Facility Data Defect Development Diagnosis Dietary Supplementation Disease Embryo Ensure Family Folic Acid Genes Genetic Genetic Engineering Genetic Transcription Genotype Geography Goals Heritability Human Hydrocephalus Incidence Inherited International Knock-in Knock-out Knowledge Learning Disabilities Life Live Birth Measures Meningomyelocele Modeling Molecular Molecular Genetics Monitor Morbidity - disease rate Mus Mutate Mutation Network-based Neural Tube Closure Neural Tube Defects Neuraxis Outcome Patients Penetrance Phenotype Population Proteins Protocols documentation Rana Recurrence Research Research Personnel Risk Risk Factors Role Running Secure Seizures Source Spinal Dysraphism Structural Congenital Anomalies Technology United States National Institutes of Health Variant Work Xenopus Xenopus laevis cohort computerized data processing computerized tools cost estimate data harmonization data quality de novo mutation design dietary disability disease mechanisms study disorder prevention disorder risk epigenome epigenomics exome folic acid supplementation fortification gene environment interaction gene interaction genome sequencing human model improved inclusion criteria interest mortality mutant neuromechanism next generation sequencing programs recruit relating to nervous system risk variant social media tool transcriptome whole genome

Affect Alleles American Animal Model Attention Bioinformatics Brain Stem Candidate Disease Gene Child Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Communication Communities Congenital Abnormality Country Custom DNA DNA Methylation DNA Sequence Alteration DNA Sequencing Facility Data Defect Development Diagnosis Dietary Supplementation Disease Embryo Ensure Family Folic Acid Genes Genetic Genetic Engineering Genetic Transcription Genotype Geography Goals Heritability Human Hydrocephalus Incidence Inherited International Knock-in Knock-out Knowledge Learning Disabilities Life Live Birth Measures Meningomyelocele Modeling Molecular Molecular Genetics Monitor Morbidity - disease rate Mus Mutate Mutation Network-based Neural Tube Closure Neural Tube Defects Neuraxis Outcome Patients Penetrance Phenotype Population Proteins Protocols documentation Rana Recurrence Research Research Personnel Risk Risk Factors Role Running Secure Seizures Source Spinal Dysraphism Structural Congenital Anomalies Technology United States National Institutes of Health Variant Work Xenopus Xenopus laevis cohort computerized data processing computerized tools cost estimate data harmonization data quality de novo mutation design dietary disability disease mechanisms study disorder prevention disorder risk epigenome epigenomics exome folic acid supplementation fortification gene environment interaction gene interaction genome sequencing human model improved inclusion criteria interest mortality mutant neuromechanism next generation sequencing programs recruit relating to nervous system risk variant social media tool transcriptome whole genome

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项目摘要

Project Summary – Overall: Developmental Mechanisms of Human Meningomyelocele The central goal of this Program Project application is to understand mechanisms of Meningomyelocele (MM), the most severe neural tube defect (NTD) compatible with survival, a condition in which folic acid (FA) fortification has had a major impact on disease risk. This PPG is designed to advance biomedical knowledge and make a high impact on our understanding of the molecular genetics of MM across the evolutionary scale, with the purpose of advancing our ability to determine disease risk, and establish mechanisms by which FA alters risk. MM is the most common birth defect of the central nervous system, affecting 3.7 per 10,000 live births, and is one of the high impact conditions prioritized by the NIH for research. In our preliminary data we have: 1] Constructed a cohort of over 1500 human trios with MM, stratified by whether the child was conceived in a FA-supplemented geography. 2] Established Xenopus laevis as a high-throughput model to assess human mutant alleles, gene-gene interactions, and FA exposure. 3] Established a number of murine NTD models with measured effect of FA on penetrance and expressivity. 4] Demonstrated a proven track record of applying these tools to study mechanisms of disease. As a result of the extensive preliminary data presented below, we have formulated this PPG with a two-fold thrust: 1] By taking advantage of the technical revolution in next generation sequencing and CRISPR genetic engineering, we will uncover and functionally assess new MM risk factors. 2] By comparing phenotypes across the evolutionary timescale, we will enhance our understanding of the basic mechanisms of NTDs and the impact of FA. The central theme running throughout the application is Gene-Environment Interaction (GXE), because of the important role FA has on MM risk in human, mouse and frog, and because the theme applies to all three Projects and Cores. Three Cores will carry out essential functions and benefit each Project. 1] Administrative Core to facilitate communication and provide opportunities for scientific collaboration. 2] Epigenomics Sequencing Core to provide essential functions in assessing FA-dependent DNA methylation and other impacts on chromatin and transcription. 3] Bioinformatics Core to provide essential functions in data processing and harmonization, mutation identification, and custom computational solutions. Specific Aims of the PPG are: 1] To uncover a host of new developmental causes of MM from this unique human cohort, as well as from mouse and frog models. 2] To explore mechanisms by which FA reduces disease incidence in human, mouse and frog. 3] To utilize mechanisms uncovered in mouse and frog NTD models to inform gene prioritization in human MM. We believe that this PPG will have a major impact on our understanding of the cellular and molecular mechanisms underlying NTDs, taking advantage of new breakthrough technology, and will set the stage for improved diagnosis and ultimately prevention of disease.

项目摘要 - 总体：人类脑膜电视球的发育机制该计划项目应用的核心目标是了解脑膜纤维膨胀机制（MM），，最严重的神经管缺陷（NTD）与生存兼容，叶酸（FA）防御能力对疾病风险产生了重大影响。该PPG旨在提高生物医学知识并对我们对整个进化量表MM分子遗传学的理解产生高影响，为了提高我们确定疾病风险的能力，并建立FA的机制改变风险。 MM是中枢神经系统最常见的先天缺陷，每10,000 Live影响3.7 出生，是NIH优先研究的高影响条件之一。在我们的初步数据中有：1]与MM建造了1500多个人类三重奏的队列，由孩子是否为在FA补充的地理位置中构思。 2]建立了Xenopus laevis作为高通量模型评估人类突变等位基因，基因 - 基因相互作用和FA暴露。 3]建立了许多鼠NTD模型具有FA对渗透和表现力的影响。 4]证明了一个经过验证的将这些工具应用于研究疾病机制的记录。由于广泛的初步下面介绍的数据，我们通过利用了两倍的推力来制定该PPG：1] 下一代测序和CRISPR基因工程的技术革命，我们将发现并在功能上评估新的MM风险因素。 2]通过比较整个进化时间尺度的表型，我们将增强我们对NTD的基本机制和FA影响的理解。中心主题在整个应用程序中运行是基因环境相互作用（GXE），因为重要作用 FA在人，鼠标和青蛙中具有MM风险，并且因为该主题适用于所有三个项目和核心。三个核心将执行基本功能并使每个项目受益。 1]行政核心促进沟通并为科学合作提供机会。 2]表观基因组学测序核心在评估FA依赖性DNA甲基化以及对染色质和其他影响方面提供了重要功能转录。 3]生物信息学核心为数据处理和协调提供基本功能，突变识别和自定义计算解决方案。 PPG的具体目的是：1]从这个独特的角度发现MM的许多新发展原因人类队列以及小鼠和青蛙模型。 2]探索FA减少的机制人，小鼠和青蛙的疾病。 3]利用鼠标和青蛙NTD中发现的机制为人类MM中基因优先次序的模型。我们认为，该PPG将对我们的了解NTD的细胞和分子机制，利用新的优势突破性技术，并将为改善诊断和最终预防疾病的阶段奠定基础。