PROJECT II: Vertebrate Animal Models of Cornelia de Lange Syndrome

项目二:Cornelia de Lange 综合征的脊椎动物模型

基本信息

  • 批准号:
    8378230
  • 负责人:
  • 金额:
    $ 50.67万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-02-01 至 2016-01-31
  • 项目状态:
    已结题

项目摘要

Cornelia de Lange Syndrome (CdLS) is a multi-organ system constellation of birth defects caused by dysfunction of cohesin, a protein complex required for chromosome cohesion, and recently implicated in the regulation of gene expression. This work will continue the development and analysis of two animal models of A//pib/-deficiency, the most common genetic cause of CdLS. The Nipbl+I- mouse replicates many features of CdLS including a high frequency of cardiac septal abnormalities. The A//pW-morphant zebrafish also displays cardiac defects, as well as gut defects that are typical of CdLS. In both systems, Nipbl deficiency appears to cause hundreds of relatively small, often tissue-specific, changes in gene expression, just as has been seen in cell lines from individuals with CdLS. The goal of the proposed work is to exploit the mouse and fish models to (1) understand the origins of heart defects in CdLS, and (2) determine the extent to which major structural defects in CdLS have a combinatorial etiology-i.e. arise as the result of synergistic interactions among small changes in the expression of multiple genes. The first aim will be accomplished using newly-developed transgenic mouse lines that harbor conditional/invertible (FLEx) alleles of Nipbl, which may be successively toggled from functionally-mutant to wildtype, and back again to mutant. Using these mouse lines, the timing and cell type(s) of origin of cardiac septal defects will be pinpointed, and potentially causal changes in gene expression identified. The second aim will be accomplished using a zebrafish model of CdLS. Experiments in this aim will focus on the identification of new potential Nipbl "target" genes, and the quantitative manipulation of their expression during early embryogenesis. Accomplishing these aims should not only aid in understanding, treating and/or preventing birth defects in CdLS; it is also likely to provide novel insights into the origins of non-syndromic birth defects, which are much more common, but may also frequently result from combinatorial interactions among small-effect alleles in the general population. RELEVANCE (See instructions): The impact of structural birth defects on human health is enormous. Animal models of Cornelia de Lange Syndrome (CdLS) will be exploited to generate new insights into the origins of birth defects, especially those of the heart and gut. Because of the way the gene defect underlying this syndrome works, there is a good probability that the results obtained will be directly relevant to common causes of birth defects in the general population.
科尔内利亚德兰格综合征(CdLS)是一种多器官系统的出生缺陷星座, cohesin是一种蛋白质复合物,是染色体凝聚所必需的, 基因表达的调控。这项工作将继续发展和分析两种动物 A//pib/-缺陷的模型,CdLS最常见的遗传原因。Nipbl+I-小鼠重复 CdLS的许多特征包括心脏间隔异常的高频率。A//pW-吗啡肽 斑马鱼还表现出心脏缺陷以及CdLS典型的肠道缺陷。在这两个系统中, 乳头缺乏似乎引起数百个相对较小的,通常是组织特异性的基因改变, 表达,正如在来自CdLS个体的细胞系中所见。拟议工作的目标 是利用小鼠和鱼类模型(1)了解CdLS心脏缺陷的起源,以及(2) 确定CdLS中的主要结构缺陷具有组合病因学的程度-即 这是多个基因表达的微小变化之间协同作用的结果。的 第一个目标将使用新开发的转基因小鼠品系来实现, Nippl的条件/可逆(FLEx)等位基因,其可以从功能突变体连续切换到 到野生型,再回到突变型。使用这些小鼠系,确定了细胞分化的时间和细胞类型。 心脏间隔缺损将被精确定位,基因表达的潜在因果变化将被确定。 第二个目标将使用CdLS的斑马鱼模型来实现。这方面的实验将集中在 新的潜在Nippl“靶”基因的鉴定,以及它们的定量操作, 在胚胎发育早期表达。 实现这些目标不仅有助于了解、治疗和/或预防出生缺陷, 它也可能为非综合征性出生缺陷的起源提供新的见解, 更常见,但也可能经常由小效应之间的组合相互作用引起。 在一般人群中。 相关性(参见说明): 结构性出生缺陷对人类健康的影响是巨大的。科尔内利亚de Lange的动物模型 综合征(CdLS)将被利用,以产生新的见解出生缺陷的起源,特别是 心脏和内脏由于这种综合症背后的基因缺陷的作用方式, 获得的结果很有可能与出生缺陷的常见原因直接相关, 一般人。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Arthur D Lander其他文献

Arthur D Lander的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Arthur D Lander', 18)}}的其他基金

Mathematical, Computational and Systems Biology
数学、计算和系统生物学
  • 批准号:
    10642829
  • 财政年份:
    2020
  • 资助金额:
    $ 50.67万
  • 项目类别:
Mentor Training to enhance mentorship in an interdisciplinary training program
导师培训旨在加强跨学科培训计划中的指导
  • 批准号:
    10393853
  • 财政年份:
    2020
  • 资助金额:
    $ 50.67万
  • 项目类别:
Mathematical, Computational and Systems Biology
数学、计算和系统生物学
  • 批准号:
    10172935
  • 财政年份:
    2020
  • 资助金额:
    $ 50.67万
  • 项目类别:
Mathematical, Computational and Systems Biology
数学、计算和系统生物学
  • 批准号:
    10430156
  • 财政年份:
    2020
  • 资助金额:
    $ 50.67万
  • 项目类别:
Systems Biology Core
系统生物学核心
  • 批准号:
    10199940
  • 财政年份:
    2019
  • 资助金额:
    $ 50.67万
  • 项目类别:
Systems Biology Core
系统生物学核心
  • 批准号:
    10385798
  • 财政年份:
    2019
  • 资助金额:
    $ 50.67万
  • 项目类别:
Systems Biology Core
系统生物学核心
  • 批准号:
    10618820
  • 财政年份:
    2019
  • 资助金额:
    $ 50.67万
  • 项目类别:
Outreach Core
外展核心
  • 批准号:
    10392895
  • 财政年份:
    2018
  • 资助金额:
    $ 50.67万
  • 项目类别:
Complexity, Cooperation and Community in Cancer
癌症的复杂性、合作和社区
  • 批准号:
    10392892
  • 财政年份:
    2018
  • 资助金额:
    $ 50.67万
  • 项目类别:
A National Short Course in Systems Biology: Tackling Spatial Dynamics in Cells an
系统生物学国家短期课程:解决细胞中的空间动力学和
  • 批准号:
    8310057
  • 财政年份:
    2011
  • 资助金额:
    $ 50.67万
  • 项目类别:

相似海外基金

Linkage of HIV amino acid variants to protective host alleles at CHD1L and HLA class I loci in an African population
非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
  • 批准号:
    502556
  • 财政年份:
    2024
  • 资助金额:
    $ 50.67万
  • 项目类别:
Olfactory Epithelium Responses to Human APOE Alleles
嗅觉上皮对人类 APOE 等位基因的反应
  • 批准号:
    10659303
  • 财政年份:
    2023
  • 资助金额:
    $ 50.67万
  • 项目类别:
Deeply analyzing MHC class I-restricted peptide presentation mechanistics across alleles, pathways, and disease coupled with TCR discovery/characterization
深入分析跨等位基因、通路和疾病的 MHC I 类限制性肽呈递机制以及 TCR 发现/表征
  • 批准号:
    10674405
  • 财政年份:
    2023
  • 资助金额:
    $ 50.67万
  • 项目类别:
An off-the-shelf tumor cell vaccine with HLA-matching alleles for the personalized treatment of advanced solid tumors
具有 HLA 匹配等位基因的现成肿瘤细胞疫苗,用于晚期实体瘤的个性化治疗
  • 批准号:
    10758772
  • 财政年份:
    2023
  • 资助金额:
    $ 50.67万
  • 项目类别:
Identifying genetic variants that modify the effect size of ApoE alleles on late-onset Alzheimer's disease risk
识别改变 ApoE 等位基因对迟发性阿尔茨海默病风险影响大小的遗传变异
  • 批准号:
    10676499
  • 财政年份:
    2023
  • 资助金额:
    $ 50.67万
  • 项目类别:
New statistical approaches to mapping the functional impact of HLA alleles in multimodal complex disease datasets
绘制多模式复杂疾病数据集中 HLA 等位基因功能影响的新统计方法
  • 批准号:
    2748611
  • 财政年份:
    2022
  • 资助金额:
    $ 50.67万
  • 项目类别:
    Studentship
Recessive lethal alleles linked to seed abortion and their effect on fruit development in blueberries
与种子败育相关的隐性致死等位基因及其对蓝莓果实发育的影响
  • 批准号:
    22K05630
  • 财政年份:
    2022
  • 资助金额:
    $ 50.67万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Genome and epigenome editing of induced pluripotent stem cells for investigating osteoarthritis risk alleles
诱导多能干细胞的基因组和表观基因组编辑用于研究骨关节炎风险等位基因
  • 批准号:
    10532032
  • 财政年份:
    2022
  • 资助金额:
    $ 50.67万
  • 项目类别:
Investigating the Effect of APOE Alleles on Neuro-Immunity of Human Brain Borders in Normal Aging and Alzheimer's Disease Using Single-Cell Multi-Omics and In Vitro Organoids
使用单细胞多组学和体外类器官研究 APOE 等位基因对正常衰老和阿尔茨海默病中人脑边界神经免疫的影响
  • 批准号:
    10525070
  • 财政年份:
    2022
  • 资助金额:
    $ 50.67万
  • 项目类别:
Leveraging the Evolutionary History to Improve Identification of Trait-Associated Alleles and Risk Stratification Models in Native Hawaiians
利用进化历史来改进夏威夷原住民性状相关等位基因的识别和风险分层模型
  • 批准号:
    10689017
  • 财政年份:
    2022
  • 资助金额:
    $ 50.67万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了