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: 8323834
• 负责人: William C Mobley
• 金额: $ 64.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/8323834
• 关键词: Adult; Affect; Age; Aging; Alzheimer' s Disease; Aneuploidy; Animal Model; Behavior; Birth; Centers for Disease Control and Prevention (U.S.); Characteristics; Child; Chromosomal Rearrangement; Chromosomes; Chromosomes, Human, Pair 21; Cognition; Cognitive; Congenital Heart Defects; Dementia; Development; Developmental Delay Disorders; Dissection; Dorsal; Down Syndrome; Elderly; Engineering; Exhibits; Funding; Gene Dosage; Genes; Genetic; Genetic Models; Genomic Segment; Genomics; Genotype; Goals; Hippocampus (Brain); Human; Human Chromosomes; Impaired cognition; Impairment; Learning; Life; Link; Long-Term Potentiation; Measures; Mediating; Memory; Methodology; Modeling; Molecular; Mus; Mutant Strains Mice; Nerve Degeneration; Nervous system structure; Neurons; Orthologous Gene; Pathology; Phenotype; Play; Population; Psyche structure; Reporting; Role; Societies; Staging; Structure; Synapses; Syntenic Conservation; Testing; Trisomy; Trust; United States; age related; age related neurodegeneration; aged; basal forebrain cholinergic neurons; base; disability; effective therapy; experience; genetic analysis; innovation; interest; locus ceruleus structure; mouse Ts65Dn; mouse genome; mouse model; mutant; neurodegenerative phenotype; neuropathology; noradrenergic; public health relevance; skills; success

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。