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）：21三体唐氏综合症（DS）在美国影响了大约40万人，导致认知障碍，其中包括阿尔茨海默病和老年痴呆症的神经病理学。根据流行的基因剂量效应假说，退行性痴呆的认知相关表型是由一个或多个人类染色体（HSA） 21基因的三倍复制引起的。我们对小鼠的初步观察表明，这些致病基因确实存在，对它们的寻找是可能的，也是有成效的。本项目的长期目标是通过基于小鼠的遗传分析来识别这些致病基因，这是建立在我们团队最近的成功基础上的：(1)我们利用高效的Cre/ loxp介导的染色体工程开发了两种最佳的DS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合成区域的三体，Dp(10)1Yu/+, Dp(16)1Yu/+；Dp(17)1Yu/+，在MMU10、MMU16和MMU17上的三个HSA21同区都是三体的。(2)我们已经将与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基因同源物的Cbr1-Fam3b染色体片段。这段基因在小鼠体内的重复会导致认知行为、突触结构和海马长期增强（海马长期增强是学习和记忆的主要细胞机制）的异常。为了实现我们的目标，我们在本应用的Specific Aim 1中提出，表征最重要的认知相关表型的最佳参考小鼠模型。为了建立基本表型参数，便于基因解剖，我们将对Dp(16)1Yu/+、Dp(10)1Yu/+、Dp(16)1Yu/+、Dp(16)1Yu/+、Dp(16)1Yu/+、Dp(16)1Yu/+、Dp(16)1Yu/+、Dp(16)1Yu/+、Dp(16)1Yu/+、Dp(16)1Yu/+的海马突触结构、可塑性和认知行为进行表征。余Dp(17) 1 / +老鼠。我们还将测量不同年龄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Specific Aim 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新的小鼠突变体，在Cbr1-Fam3b片段中携带嵌套的重复和缺失，通过使用这些突变体，我们将采用减/加策略，其中突触和认知表型与越来越小的基因组片段相关联，直到最小临界区域被定义。这项工作将为确定这些表型的最小临界区域内的致病基因奠定基础，这将为揭示ds相关认知障碍的分子机制奠定基础，并为上述假设提供结论性支持。因此，我们期望通过这些研究，大大加快对退行性椎体滑移认知障碍的理解和治疗进展。