Epigenetics of Down Syndrome

唐氏综合症的表观遗传学

• 批准号: 9898045
• 负责人: Benjamin Tycko
• 金额: $ 60.24万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/9898045
• 关键词: AD pathology; Address; Adult; Affect; Age; Age of Onset; Age-associated memory impairment; Aging; Alzheimer' s Disease; Amyloid Beta A4 Precursor Protein; Behavioral Paradigm; Biological Aging; Biological Assay; Biological Markers; Bone Marrow; Brain; Candidate Disease Gene; Cells; Cerebrum; Chromosomal Duplication; Chromosomes; Chromosomes, Human, Pair 10; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 21; Complex; DNA Methylation; Development; Disease; Dissection; Down Syndrome; Engineering; Epigenetic Process; Exhibits; Foundations; Future; Gene Dosage; General Population; Genes; Genetic; Genetic Crosses; Genetic Fingerprintings; Goals; Hematopoietic stem cells; Hippocampus (Brain); Home environment; Human; Human Chromosomes; Immune system; Impaired cognition; Individual; Kinetics; Learning; Link; Long-Term Potentiation; Measures; Medical; Memory; Modeling; Molecular; Mus; Nerve Degeneration; Orthologous Gene; Other Genetics; Pathology; Pattern; Phenotype; Population; Process; Reagent; Research Personnel; Role; Standardization; Synapses; Syntenic Conservation; T-Lymphocyte; Therapeutic Studies; age related; aging auditory system; base; bisulfite sequencing; causal variant; clinical phenotype; density; dosage; early onset; experimental study; gray matter; hearing impairment; molecular marker; mouse model; non-genetic; parent grant; premature; response; transcriptome; transcriptome sequencing; transcriptomics

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.

此申请是针对NOT-OD-19-071提交的。在我们的MPI R01家长资助中 《唐氏综合征的表观遗传学》，我们正在用小鼠模型来研究唐氏综合征的改变机制 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。在这一补充/修订应用中，我们建议研究表观遗传和生物衰老以及 使用我们的节段性复制小鼠，这些过程在共同发生的年龄相关疾病中的作用 DS的模型，即DP(10)1Yey和DP(16)1Yey，其中包含 小鼠10号和16号染色体(Mm10、Mm16)与人类21号染色体具有保守的同源性 (Hsa21)。要研究的具有医学意义的表型是与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衰退(与阿尔茨海默病无关)。 我们认为使用DP(10)和DP(16)小鼠模型，以及DP(16)小鼠带有App基因的剂量 归一化到解剖，我们可以开始使用基因解剖来帮助我们回答以下问题：(I) 什么是Hsa21上导致DS早期表观遗传老化的基因？(Ii)Hsa21上有哪些基因 引起DS的早期生物衰老(III)表观遗传衰老仅仅是一个有用的“时钟”，还是做表观遗传变化 在功能上影响生物衰老？以及(Iv)早期生物衰老是否有助于提早发病 DS患者的免疫系统缺陷、听力损失和认知功能下降(与AD无关)？我们有两个 具体目标：(1)通过甲基-seq和rna-seq对上述模型的脑细胞和免疫系统细胞进行定义 年龄，我们将询问在这些节段性模型中是否发生早期表观遗传衰老，以及这是否 这一现象需要两个染色体区域的复制。(2)通过对前述临床病例的分析 在与目标1相同年龄的相同小鼠模型中，我们将确定是否 Mmu10和Mmu16上Hsa21共线区的重复会影响这些年龄相关的表型。喜欢 在人类中，App基因的三重复制是DS小鼠表现出阿尔茨海默型神经退行性变的必要条件。通过 将节段性复制小鼠的App基因剂量归一化为两个拷贝，我们将确定 通过使用突触密度分析，认知能力下降的早期衰老，独立于AD的病理， 海马长时程增强与不同年龄学习记忆的行为范式。 这些目标的实现将为鉴定导致早期感染的hsa21基因同源基因(S)奠定基础。 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，以及AD非依赖性认知能力下降。这些结果将对理解和 改善DS患者的共生情况并改善这些相同的问题 一般(整倍体)种群。