Genetic Basis of Failed Cognition in Young and Aged Mouse Models of Trisomy 21

21 三体年轻和老年小鼠模型认知失败的遗传基础

基本信息

  • 批准号:
    8323834
  • 负责人:
  • 金额:
    $ 64.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-09-30 至 2015-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Trisomy 21, Down syndrome (DS), affects approximately 400,000 people in the U.S., causing cognitive disability, which includes the neuropathology of Alzheimer's disease and late-life dementia. Based on the prevailing gene dosage effect hypothesis, a cognitively relevant phenotype in DS is caused by the triplication of one or more human chromosome (HSA) 21 genes. Our preliminary observations from the mouse-based studies suggest that these causative genes are indeed present and the search for them is both possible and productive. The long-term objective of this project is to identify these causative genes by using mouse-based genetic analysis, which is built upon the recent successes of our team: (1) We have developed two optimal reference mouse models for DS using efficient Cre/loxP-mediated chromosome engineering: Dp(16)1Yu/+, which is trisomic for the entire 22.9-Mb HSA21 syntenic region on mouse chromosome (MMU) 16, and Dp(10)1Yu/+;Dp(16)1Yu/+;Dp(17)1Yu/+, which is trisomic for all three HSA21 syntenic regions on MMU10, MMU16 and MMU17. (2) We have narrowed down the genomic region associated with the cognitive disability of DS to the smallest segment in the mouse genome: the Cbr1-Fam3b chromosomal segment containing 30 HSA21 gene orthologs. The triplication of this segment in mice causes abnormalities in cognitive behaviors, synaptic structures and hippocampal long-term potentiation, a major cellular mechanism that underlies learning and memory. To achieve our objective, we propose, in Specific Aim 1 of this application, to characterize the most important cognitively relevant phenotypes of the optimal reference mouse models for DS. To establish the basic phenotypic parameters to facilitate the genetic dissection, we will characterize the synaptic structures and plasticity in the hippocampus as well as cognitive behaviors of Dp(16)1Yu/+ and Dp(10)1Yu/+;Dp(16)1Yu/+;Dp(17)1Yu/+ mice. We will also measure the size and number of neurons in the hippocampal circuits of Dp(16)1/+ mice at the different ages to ascertain the neurodegenerative phenotype. In Specific Aim 2, we will analyze the Cbr1-Famb3b segment to identify a minimal genomic region for the DS- associated synaptic and cognitive phenotypes. We will generate new mouse mutants carrying nested duplications and deletions within the Cbr1-Fam3b segment by chromosome engineering and, by using these mutants, we will employ a subtractive/additive strategy in which synaptic and cognitive phenotypes are linked to progressively smaller genomic segments until a minimal critical region is defined. This effort will lay the groundwork to identify a causative gene(s) located within the minimal critical region(s) for these phenotypes, which will set the stage for the unraveling of the molecular mechanism of DS-associated cognitive disability as well as provide the conclusive support for the aforementioned hypothesis. Therefore, we expect, through these studies, to considerably accelerate progress in understanding and treating cognitive disability in DS. PUBLIC HEALTH RELEVANCE: Cognitive dysfunction affects essentially all children and adults with trisomy 21, Down syndrome (DS); with no effective treatments available, fully 400,000 people in the U.S. experience developmental delays in mental function as children and progressive decline of cognitive skills associated with the neuropathology of Alzheimer's disease during aging. Innovative approaches to unraveling the underlying mechanisms and to developing effective therapies are urgently needed. We propose to use chromosome engineering to create new mouse mutants to define linkages between cognitively relevant phenotypes of DS and minimal critical genomic regions, with the ultimate goal of identifying the causative genes, an accomplishment that would greatly accelerate progress toward understanding and treating cognitive dysfunction in DS.
描述(由申请人提供):21 三体症,即唐氏综合症 (DS),影响着美国大约 400,000 人,导致认知障碍,其中包括阿尔茨海默病和晚年痴呆的神经病理学。根据流行的基因剂量效应假说,DS 中与认知相关的表型是由一个或多个人类染色体 (HSA) 21 基因的三倍体引起的。我们对小鼠研究的初步观察表明,这些致病基因确实存在,并且对它们的寻找是可能的且富有成效的。该项目的长期目标是通过使用基于小鼠的遗传分析来识别这些致病基因,该分析建立在我们团队最近取得的成功的基础上:(1)我们使用高效的 Cre/loxP 介导的染色体工程开发了两种 DS 的最佳参考小鼠模型:Dp(16)1Yu/+,它是小鼠染色体 (MMU) 16 上整个 22.9-Mb HSA21 同线区域的三体性,以及 Dp(10)1Yu/+;Dp(16)1Yu/+;Dp(17)1Yu/+,对于 MMU10、MMU16 和 MMU17 上的所有三个 HSA21 同线区域都是三体性的。 (2)我们将与DS认知障碍相关的基因组区域缩小到小鼠基因组中最小的片段:包含30个HSA21基因直向同源物的Cbr1-Fam3b染色体片段。小鼠中该片段的三倍化会导致认知行为、突触结构和海马长时程增强(学习和记忆的主要细胞机制)的异常。 为了实现我们的目标,我们建议在本申请的具体目标 1 中描述 DS 最佳参考小鼠模型最重要的认知相关表型。为了建立基本表型参数以促进遗传解剖,我们将表征 Dp(16)1Yu/+ 和 Dp(10)1Yu/+;Dp(16)1Yu/+;Dp(17)1Yu/+ 小鼠的海马突触结构和可塑性以及认知行为。我们还将测量不同年龄的 Dp(16)1/+ 小鼠海马回路中神经元的大小和数量,以确定神经退行性表型。在具体目标 2 中,我们将分析 Cbr1-Famb3b 片段,以确定 DS 相关突触和认知表型的最小基因组区域。我们将通过染色体工程产生在 Cbr1-Fam3b 片段内携带嵌套重复和缺失的新小鼠突变体,并且通过使用这些突变体,我们将采用减法/加法策略,其中突触和认知表型与逐渐较小的基因组片段相关联,直到定义最小关键区域。这项工作将为确定这些表型最小关键区域内的致病基因奠定基础,这将为阐明 DS 相关认知障碍的分子机制奠定基础,并为上述假设提供决定性支持。因此,我们期望通过这些研究,大大加快了解和治疗 DS 认知障碍的进展。 公共卫生相关性:认知功能障碍基本上影响所有患有 21 三体症、唐氏综合症 (DS) 的儿童和成人;由于没有有效的治疗方法,美国有整整 400,000 人在儿童时期经历了心理功能发育迟缓,并且在衰老过程中与阿尔茨海默病的神经病理学相关的认知能力逐渐下降。迫切需要创新方法来揭示潜在机制并开发有效的疗法。我们建议使用染色体工程来创建新的小鼠突变体,以定义 DS 认知相关表型和最小关键基因组区域之间的联系,最终目标是识别致病基因,这一成就将大大加速理解和治疗 DS 认知功能障碍的进展。

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 }}

William C Mobley其他文献

A novel mechanism underlying pathogenesis of Down syndrome
  • DOI:
    10.1186/1750-1326-8-s1-o23
  • 发表时间:
    2013-09-01
  • 期刊:
  • 影响因子:
    17.500
  • 作者:
    Xin Wang;Yingjun Zhao;Xiaofei Zhang;Ying Zhou;Barbara Ranscht;Fred H Gage;William C Mobley;Yun-wu Zhang;Stuart A Lipton;Wanjin Hong;Huaxi Xu
  • 通讯作者:
    Huaxi Xu
Pathologic Involvement of Interneurons in Mouse Models of Neuronal Ceroid Lipofuscinosis
神经元蜡样质脂褐质沉积症小鼠模型中中间神经元的病理性受累
  • DOI:
    10.1203/00006450-199904020-02021
  • 发表时间:
    1999-04-01
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Jonathan D Cooper;William C Mobley
  • 通讯作者:
    William C Mobley

William C Mobley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('William C Mobley', 18)}}的其他基金

Antisense Oligonucleotides targeting APP to prevent neurodegeneration in models of Down Syndrome and Alzheimer's disease
靶向 APP 的反义寡核苷酸可预防唐氏综合症和阿尔茨海默病模型中的神经变性
  • 批准号:
    10554249
  • 财政年份:
    2019
  • 资助金额:
    $ 64.55万
  • 项目类别:
Antisense Oligonucleotides targeting APP to prevent neurodegeneration in models of Down Syndrome and Alzheimer's disease
靶向 APP 的反义寡核苷酸可预防唐氏综合症和阿尔茨海默病模型中的神经变性
  • 批准号:
    10543710
  • 财政年份:
    2019
  • 资助金额:
    $ 64.55万
  • 项目类别:
Antisense Oligonucleotides targeting APP to prevent neurodegeneration in models of Down Syndrome and Alzheimer's disease
靶向 APP 的反义寡核苷酸可预防唐氏综合症和阿尔茨海默病模型中的神经变性
  • 批准号:
    9905472
  • 财政年份:
    2019
  • 资助金额:
    $ 64.55万
  • 项目类别:
Antisense Oligonucleotides targeting APP to prevent neurodegeneration in models of Down Syndrome and Alzheimer's disease
靶向 APP 的反义寡核苷酸可预防唐氏综合症和阿尔茨海默病模型中的神经变性
  • 批准号:
    10334410
  • 财政年份:
    2019
  • 资助金额:
    $ 64.55万
  • 项目类别:
Antisense Oligonucleotides targeting APP to prevent neurodegeneration in models of Down Syndrome and Alzheimer's disease
靶向 APP 的反义寡核苷酸可预防唐氏综合症和阿尔茨海默病模型中的神经变性
  • 批准号:
    10092057
  • 财政年份:
    2019
  • 资助金额:
    $ 64.55万
  • 项目类别:
Treating with Gamma-Secretase Modulators to Prevent Neurodegeneration in Mouse Models of Down Syndrome and Alzheimer Disease
使用γ-分泌酶调节剂治疗以预防唐氏综合症和阿尔茨海默病小鼠模型的神经退行性变
  • 批准号:
    10338158
  • 财政年份:
    2018
  • 资助金额:
    $ 64.55万
  • 项目类别:
Alzheimer's Disease Cooperative Study
阿尔茨海默病合作研究
  • 批准号:
    9021933
  • 财政年份:
    2015
  • 资助金额:
    $ 64.55万
  • 项目类别:
NEURONAL AXONS (AXONS FROM DRG NEURONS)
神经元轴突(来自 DRG 神经元的轴突)
  • 批准号:
    8361107
  • 财政年份:
    2011
  • 资助金额:
    $ 64.55万
  • 项目类别:
Genetic Basis of Failed Cognition in Young and Aged Mouse Models of Trisomy 21
21 三体年轻和老年小鼠模型认知失败的遗传基础
  • 批准号:
    8145581
  • 财政年份:
    2010
  • 资助金额:
    $ 64.55万
  • 项目类别:
Genetic Basis of Failed Cognition in Young and Aged Mouse Models of Trisomy 21
21 三体年轻和老年小鼠模型认知失败的遗传基础
  • 批准号:
    8725237
  • 财政年份:
    2010
  • 资助金额:
    $ 64.55万
  • 项目类别:

相似海外基金

Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
  • 批准号:
    495182
  • 财政年份:
    2023
  • 资助金额:
    $ 64.55万
  • 项目类别:
Investigating how alternative splicing processes affect cartilage biology from development to old age
研究选择性剪接过程如何影响从发育到老年的软骨生物学
  • 批准号:
    2601817
  • 财政年份:
    2021
  • 资助金额:
    $ 64.55万
  • 项目类别:
    Studentship
RAPID: Coronavirus Risk Communication: How Age and Communication Format Affect Risk Perception and Behaviors
RAPID:冠状病毒风险沟通:年龄和沟通方式如何影响风险认知和行为
  • 批准号:
    2029039
  • 财政年份:
    2020
  • 资助金额:
    $ 64.55万
  • 项目类别:
    Standard Grant
Neighborhood and Parent Variables Affect Low-Income Preschool Age Child Physical Activity
社区和家长变量影响低收入学龄前儿童的身体活动
  • 批准号:
    9888417
  • 财政年份:
    2019
  • 资助金额:
    $ 64.55万
  • 项目类别:
The affect of Age related hearing loss for cognitive function
年龄相关性听力损失对认知功能的影响
  • 批准号:
    17K11318
  • 财政年份:
    2017
  • 资助金额:
    $ 64.55万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9320090
  • 财政年份:
    2017
  • 资助金额:
    $ 64.55万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    10166936
  • 财政年份:
    2017
  • 资助金额:
    $ 64.55万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9761593
  • 财政年份:
    2017
  • 资助金额:
    $ 64.55万
  • 项目类别:
How age dependent molecular changes in T follicular helper cells affect their function
滤泡辅助 T 细胞的年龄依赖性分子变化如何影响其功能
  • 批准号:
    BB/M50306X/1
  • 财政年份:
    2014
  • 资助金额:
    $ 64.55万
  • 项目类别:
    Training Grant
Inflamm-aging: What do we know about the effect of inflammation on HIV treatment and disease as we age, and how does this affect our search for a Cure?
炎症衰老:随着年龄的增长,我们对炎症对艾滋病毒治疗和疾病的影响了解多少?这对我们寻找治愈方法有何影响?
  • 批准号:
    288272
  • 财政年份:
    2013
  • 资助金额:
    $ 64.55万
  • 项目类别:
    Miscellaneous Programs
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了