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.
项目摘要 – 总体:人类脑膜脊髓膨出的发育机制 该计划项目申请的中心目标是了解脑膜脊髓膨出 (MM) 的机制, 与生存相容的最严重的神经管缺陷(NTD),在这种情况下叶酸(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 并对我们在整个进化尺度上对多发性骨髓瘤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 的机制 改变风险。 MM 是最常见的中枢神经系统出生缺陷,每 10,000 名活人中就有 3.7 人受影响 出生率,是 NIH 优先研究的高影响条件之一。在我们的初步数据中,我们 有:1] 构建了一个由超过 1500 名 MM 人类三人组组成的队列,根据孩子是否患有 MM 进行分层 在 FA 补充的地理中构思。 2]建立非洲爪蟾高通量模型 评估人类突变等位基因、基因间相互作用和 FA 暴露。 3]建立了一批 测量 FA 对外显率和表达率影响的小鼠 NTD 模型。 4] 展示了经过验证的 应用这些工具研究疾病机制的记录。经过广泛的前期工作 根据下面提供的数据,我们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,我们将发现并 功能评估新的 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 基本机制和 FA 影响的理解。中心主题 贯穿整个应用程序的是基因-环境相互作用(GXE),因为其重要作用 FA 对人类、小鼠和青蛙具有 MM 风险,因为该主题适用于所有三个项目和核心。 三个核心将履行基本职能并使每个项目受益。 1] 行政核心以促进 交流并提供科学合作的机会。 2] 表观基因组测序核心 提供评估 FA 依赖性 DNA 甲基化和对染色质的其他影响的基本功能 转录。 3] 生物信息学核心提供数据处理和协调的基本功能, 突变识别和定制计算解决方案。 PPG 的具体目标是: 1] 从这一独特的机制中揭示 MM 的一系列新的发展原因。 人类队列以及小鼠和青蛙模型。 2]探索FA减少的机制 人类、小鼠和青蛙的疾病发病率。 3] 利用小鼠和青蛙 NTD 中发现的机制 为人类 MM 中的基因优先级提供信息的模型。我们相信这次PPG将对我们产生重大影响 了解 NTD 的细胞和分子机制,利用新的 突破性技术,将为改进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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