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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

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.

项目总结-总体：人类脊膜膨出的发育机制