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; 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.

该申请正在响应于NOT-OD-19-071。在我们的MPI R01父母赠款中 “唐氏综合症的表观遗传学”，我们正在使用鼠标模型来解决改变的机制 唐氏综合症（DS）的表观遗传模式以及表观遗传变化如何影响发育 表型。在此补充/修订应用中，我们建议研究表观遗传学和生物衰老以及 这些过程使用我们的分段复制鼠标在同时发生的年龄相关条件下的作用 DS的模型，即DP（10）1yey＆dp（16）1yey，其中包含区域的分段重复 小鼠染色体10和16（MM10，MM16）与人类染色体21 （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， 依赖年龄的听力损失和年龄依赖性认知能力下降（独立于阿尔茨海默氏病，AD）。 我们认为，使用DP（10）和DP（16）鼠标模型，以及使用APP基因剂量的DP（16）小鼠 正常于疾病，我们可以开始使用遗传解剖来帮助我们回答以下问题：（i） HSA21上引起早期表观遗传衰老的基因是什么？ （ii）HSA21上的基因是什么 DS（III）中的早期生物学衰老只是表观遗传衰老，只是一个有用的“时钟”，或进行表观遗传学变化 在功能上影响生物衰老？ （iv）早期生物老化对早期发作做出了贡献 免疫系统定义DS中定义，听力损失和认知能力下降（独立于AD）？我们有两个 具体目的：（1）由上述模型的大脑和免疫系统细胞的甲基序列和RNA序列定义 年龄，我们将询问是否在这些分段模型中发生早期表观遗传衰老，以及这是否发生 现象需要重复两个染色体区域。 （2）通过分析优先提前的临床 与AIM 1相同的年龄相同的小鼠模型中的表型，我们将确定是否确定 HSA21在MMU10和MMU16上的同时区域的重复会影响这些依赖年龄的表型。喜欢 DS中的DS是DS小鼠表现出Alzheimer型神经变性所必需的。经过 将APP基因剂量归一化为分段复制小鼠的两个副本，我们将确定 通过使用突触密度分析，对认知能力下降的早期衰老，独立于AD病理学， 成功年龄的海马长期增强和学习记忆的行为范例。 实现这些目标将为识别早期引起的HSA21基因直系同源 DS中的表观遗传和生物衰老，从而影响免疫系统改变的年龄， 听力损失和与广告无关的认知下降。这些结果将与理解和 改善DS患者的同时发生条件，并改善这些相同的问题 一般（Euploid）人口。