Epigenetics of Down Syndrome

唐氏综合症的表观遗传学

基本信息

  • 批准号:
    9898045
  • 负责人:
  • 金额:
    $ 60.24万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-13 至 2022-06-30
  • 项目状态:
    已结题

项目摘要

This application is being submitted in response to NOT-OD-19-071. In our MPI R01 parent grant “Epigenetics of Down syndrome”, we are using mouse models to address the mechanisms of altered epigenetic patterning in Down syndrome (DS), and how the epigenetic changes can affect developmental phenotypes. In this supplement/revision application, we propose to study epigenetic and biological aging and the roles of these processes in co-occurring age-related conditions, using our segmental duplication mouse models of DS, namely Dp(10)1Yey & Dp(16)1Yey, which contain segmental duplications of the regions of mouse chromosomes 10 and 16 (Mm10, Mm16) that show conserved synteny with human chromosome 21 (Hsa21). The medically significant phenotypes to be investigated are age-related immune system alterations, age-dependent hearing loss, and age-dependent cognitive decline (independently of Alzheimer’s disease, AD). We believe that using the Dp(10) and Dp(16) mouse models, and Dp(16) mice with App gene dosage normalized to disomy, we can start to use genetic dissection to help us to answer the following questions: (i) what are the genes on Hsa21 that cause early epigenetic aging in DS? (ii) what are the genes on Hsa21 that cause early biological aging in DS (iii) is epigenetic aging simply a useful “clock”, or do epigenetic changes functionally influence biological aging? and (iv) does early biological aging contribute to the early onset of immune system deficits, hearing loss, and cognitive decline (independently of AD) in DS? We have two specific aims: (1) By methyl-seq & RNA-seq of brain and immune system cells of the above models at defined ages, we will ask whether early epigenetic aging occurs in these segmental models, and whether this phenomenon requires duplication of both chromosomal regions. (2) By analyzing the aforementioned clinical phenotypes in the same mouse models at each of the same ages as in Aim 1, we will determine whether the duplications of Hsa21 syntenic regions on Mmu10 and Mmu16 affect these age-dependent phenotypes. Like DS in humans, App gene triplication is necessary for DS mice to exhibit Alzheimer-type neurodegeneration. By normalizing App gene dosage to two copies in the segmental duplication mice, we will determine the impact of early aging on cognitive decline, independently of AD pathology, by using synaptic density analysis, hippocampal long-term potentiation and behavioral paradigms of learning and memory at successive ages. Attaining these objectives will set the stage for identifying the Hsa21 gene ortholog(s) that cause early epigenetic and biological aging in DS and thereby affect the age-of-onset of immune system alterations, hearing loss, and AD-independent cognitive decline. These results will be relevant both for understanding and ameliorating co-occurring conditions in people with DS and for ameliorating these same problems in the general (euploid) population.
本申请是根据NOT-OD-19-071提交的。在我们的MPI R 01家长补助金中 “唐氏综合征的表观遗传学”,我们正在使用小鼠模型来解决改变的机制, 唐氏综合征(DS)的表观遗传模式,以及表观遗传变化如何影响发育 表型在这个补充/修订申请中,我们建议研究表观遗传和生物衰老, 这些过程在共同发生的年龄相关的条件下的作用,使用我们的节段性重复小鼠 DS的模型,即Dp(10)1 Yey和Dp(16)1 Yey,其中包含DS区域的片段重复 小鼠10号和16号染色体(Mm 10,Mm 16),与人类21号染色体显示保守的同线性 (Hsa 21)。待研究的具有医学意义的表型是年龄相关的免疫系统改变, 年龄依赖性听力损失和年龄依赖性认知下降(独立于阿尔茨海默病,AD)。 我们认为,使用Dp(10)和Dp(16)小鼠模型,以及Dp(16)小鼠与App基因剂量 标准化为二体,我们可以开始使用遗传解剖来帮助我们回答以下问题:(i) Hsa 21上的哪些基因导致了DS的早期表观遗传衰老?(ii)Hsa 21上的哪些基因 导致早期生物老化的DS(三)是表观遗传老化只是一个有用的“时钟”,或做表观遗传的变化 对生物衰老有什么影响以及(iv)早期生物老化是否有助于 DS患者的免疫系统缺陷、听力损失和认知能力下降(独立于AD)?我们有两 具体目的:(1)通过甲基-seq和RNA-seq的脑和免疫系统细胞的上述模型在定义的 年龄,我们将询问早期表观遗传衰老是否发生在这些节段模型中,以及这是否 这种现象需要两个染色体区域的重复。(2)通过分析上述临床 在与目标1相同的年龄的每个相同的小鼠模型中,我们将确定 Mmu 10和Mmu 16上Hsa 21同线区的重复影响这些年龄依赖性表型。像 在人类DS中,App基因三倍是DS小鼠表现出阿尔茨海默型神经变性所必需的。通过 将App基因剂量标准化为节段性重复小鼠中的两个拷贝,我们将确定 通过使用突触密度分析, 海马长时程增强和连续年龄的学习记忆行为模式。 实现这些目标将为鉴定Hsa 21基因直系同源物奠定基础,这些直系同源物导致早期 DS的表观遗传和生物老化,从而影响免疫系统改变的发病年龄, 听力损失和AD非依赖性认知下降。这些结果将有助于理解, 改善患有DS的人中的共同发生的状况,以及改善患有DS的人中的这些相同问题。 一般(整倍体)群体。

项目成果

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Benjamin Tycko其他文献

Benjamin Tycko的其他文献

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{{ truncateString('Benjamin Tycko', 18)}}的其他基金

Identifying and characterizing functional noncoding mutations in multiple myeloma
识别和表征多发性骨髓瘤的功能性非编码突变
  • 批准号:
    10586759
  • 财政年份:
    2023
  • 资助金额:
    $ 60.24万
  • 项目类别:
DNA Elements Underlying Celiac and Crohn's Susceptibility
乳糜泻和克罗恩病易感性的 DNA 元素
  • 批准号:
    9664318
  • 财政年份:
    2018
  • 资助金额:
    $ 60.24万
  • 项目类别:
Genetic-epigenetic and aging interactions at COVID- 19 host response loci in Down syndrome and mouse models
唐氏综合症和小鼠模型中 COVID-19 宿主反应位点的遗传-表观遗传和衰老相互作用
  • 批准号:
    10221384
  • 财政年份:
    2017
  • 资助金额:
    $ 60.24万
  • 项目类别:
Epigenetics of Down Syndrome
唐氏综合症的表观遗传学
  • 批准号:
    9977004
  • 财政年份:
    2017
  • 资助金额:
    $ 60.24万
  • 项目类别:
Epigenetics of Down Syndrome
唐氏综合症的表观遗传学
  • 批准号:
    10200867
  • 财政年份:
    2017
  • 资助金额:
    $ 60.24万
  • 项目类别:
Targeting Cancer-Associated Myofibroblasts by DNA Hypomethylation
通过 DNA 低甲基化靶向癌症相关肌成纤维细胞
  • 批准号:
    8555378
  • 财政年份:
    2011
  • 资助金额:
    $ 60.24万
  • 项目类别:
Targeting Cancer-Associated Myofibroblasts by DNA Hypomethylation
通过 DNA 低甲基化靶向癌症相关肌成纤维细胞
  • 批准号:
    8256911
  • 财政年份:
    2011
  • 资助金额:
    $ 60.24万
  • 项目类别:
Epigenetic Modifiers in Down Syndrome
唐氏综合症的表观遗传修饰剂
  • 批准号:
    7976426
  • 财政年份:
    2010
  • 资助金额:
    $ 60.24万
  • 项目类别:
Optimizing MSNP for profiling DNA methylation in cancers and precursor lesions
优化 MSNP 以分析癌症和癌前病变中的 DNA 甲基化
  • 批准号:
    7902107
  • 财政年份:
    2009
  • 资助金额:
    $ 60.24万
  • 项目类别:
Optimizing MSNP for profiling DNA methylation in cancers and precursor lesions
优化 MSNP 以分析癌症和癌前病变中的 DNA 甲基化
  • 批准号:
    7660795
  • 财政年份:
    2009
  • 资助金额:
    $ 60.24万
  • 项目类别:

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