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:
  • 金额:
    $ 139.06万
  • 依托单位:
  • 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

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:人类脊髓脊膜膨出的发育机制 本项目申请的中心目标是了解脊髓脊膜膨出(MM)的机制, 最严重的神经管缺陷(NTD)与生存相容,叶酸(FA) 强化对疾病风险产生了重大影响。该PPG旨在推进生物医学知识 并对我们在进化尺度上对MM分子遗传学的理解产生重大影响, 目的是提高我们确定疾病风险的能力,并建立FA 改变风险。MM是中枢神经系统最常见的出生缺陷,每10,000例活产中有3.7例患有MM。 出生,并且是NIH优先研究的高影响条件之一。在我们的初步数据中, 构建了一个超过1500例患有MM的人类三人组的队列,根据儿童是否患有MM进行分层。 在一个FA补充的地理中构思。2]建立非洲爪蟾作为高通量模型 评估人类突变等位基因、基因-基因相互作用和FA暴露。3]设立了若干 小鼠NTD模型,测定FA对表达率和表达率的影响。4]证明了一个 应用这些工具研究疾病机制的记录。由于广泛的初步 下面给出的数据,我们已经制定了具有双重推力的PPG:1]通过利用 下一代测序和CRISPR基因工程的技术革命,我们将揭示和 功能性评估新的MM风险因素。2]通过比较进化时间尺度上的表型, 将加深我们对NTD的基本机制和FA的影响的理解。中心主题 基因-环境相互作用(GXE)是贯穿整个应用程序的一个重要角色, FA在人类、小鼠和青蛙中没有MM风险,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 交流,提供科学合作的机会。2]表观基因组学测序核心 在评估FA依赖性DNA甲基化和对染色质的其他影响方面提供基本功能, 转录。3]生物信息学核心,提供数据处理和协调方面的基本功能, 突变识别和定制计算解决方案。 PPG的具体目的是:1]从这种独特的疾病中发现MM的许多新的发展原因。 人队列以及来自小鼠和青蛙模型。2]探索FA减少的机制 人类、小鼠和青蛙的发病率。3]利用小鼠和青蛙NTD中发现的机制 我们相信这个PPG将对我们的研究产生重大影响。 了解神经管缺陷的细胞和分子机制,利用新的 突破性的技术,并将为改善诊断和最终预防疾病奠定基础。

项目成果

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JOSEPH G GLEESON其他文献

JOSEPH G GLEESON的其他文献

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{{ truncateString('JOSEPH G GLEESON', 18)}}的其他基金

Origins of Brain Somatic Mosaicism in Developmental Brain Disease
发育性脑疾病中脑体细胞嵌合的起源
  • 批准号:
    10466904
  • 财政年份:
    2021
  • 资助金额:
    $ 139.06万
  • 项目类别:
University of California San Diego Neuroscience Microscopy Imaging Core
加州大学圣地亚哥分校神经科学显微成像核心
  • 批准号:
    10524688
  • 财政年份:
    2021
  • 资助金额:
    $ 139.06万
  • 项目类别:
Origins of Brain Somatic Mosaicism in Developmental Brain Disease
发育性脑疾病中脑体细胞嵌合的起源
  • 批准号:
    10299502
  • 财政年份:
    2021
  • 资助金额:
    $ 139.06万
  • 项目类别:
Origins of Brain Somatic Mosaicism in Developmental Brain Disease
发育性脑疾病中脑体细胞嵌合的起源
  • 批准号:
    10669715
  • 财政年份:
    2021
  • 资助金额:
    $ 139.06万
  • 项目类别:
Project I - Human genetics of meningomyelocele and risk mitigation by folic acid
项目 I - 脑膜脊髓膨出的人类遗传学和叶酸降低风险
  • 批准号:
    10300070
  • 财政年份:
    2020
  • 资助金额:
    $ 139.06万
  • 项目类别:
Developmental Mechanisms of Human Meningomyelocele
人类脑膜脊髓膨出的发生机制
  • 批准号:
    10533735
  • 财政年份:
    2020
  • 资助金额:
    $ 139.06万
  • 项目类别:
Core A - Administrative Core
核心 A - 行政核心
  • 批准号:
    10533736
  • 财政年份:
    2020
  • 资助金额:
    $ 139.06万
  • 项目类别:
Developmental Mechanisms of Human Meningomyelocele
人类脑膜脊髓膨出的发生机制
  • 批准号:
    10154461
  • 财政年份:
    2020
  • 资助金额:
    $ 139.06万
  • 项目类别:
Core A - Administrative Core
核心 A - 行政核心
  • 批准号:
    10154462
  • 财政年份:
    2020
  • 资助金额:
    $ 139.06万
  • 项目类别:
Core A - Administrative Core
核心 A - 行政核心
  • 批准号:
    10300067
  • 财政年份:
    2020
  • 资助金额:
    $ 139.06万
  • 项目类别:

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