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: 8145581
• 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/8145581
• 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，唐氏综合症（DS）的三体疾病影响美国约40万人，导致认知障碍，其中包括阿尔茨海默氏病和晚期痴呆的神经病理学。基于流行的基因剂量效应假说，DS中的认知相关表型是由一个或多个人类染色体（HSA）21基因的一式固定引起的。我们从基于小鼠的研究中进行的初步观察表明，这些因果基因确实存在，并且寻找它们既可能又有生产力。该项目的长期目标是通过使用基于鼠标的遗传分析来识别这些病因基因，这建立在我们团队的最新成功基础上：（1）我们使用有效的CRE/LOXP介导的染色体工程开发了两个最佳的DS参考鼠标模型：DP（16）1yu/+，这是整个22.9-MB HSA21 Syniic（MmB HSA21 and nores and and and and nouse nores intecy and nouse nore nou鼠标）。 dp（10）1yu/+; dp（16）1yu/+; dp（17）1yu/+，这是MMU10，MMU16和MMU17上所有三个HSA21同步区域的三异构体。 （2）我们已经缩小了与DS的认知障碍相关的基因组区域到小鼠基因组中最小的段：CBR1-FAM3B染色体段含有30个HSA21基因直系同源物。小鼠中这一段的一式序列导致认知行为，突触结构和海马长期增强的异常，这是一种主要的细胞机制，是学习和记忆的主要细胞机制。 为了实现我们的目标，我们建议在本应用的特定目的1中表征DS最佳参考小鼠模型的最重要的认知相关表型。为了建立基本的表型参数以促进遗传解剖，我们将表征海马中的突触结构和可塑性以及DP（16）1YU/+和DP（10）1yu/+; Dp（16）1yu/+; Dp（17）1yu; dp（17）1yu/+小鼠的DP（16）1YU/+和DP（10）1yu/+的认知行为。我们还将测量DP（16）1/+小鼠的海马电路中神经元的大小和数量，以确定神经退行性表型。在特定目标2中，我们将分析CBR1-FAMB3B段，以确定DS相关的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制造新的小鼠突变体，这些突变体在CBR1-FAM3B段内携带嵌套重复和缺失，并通过使用这些突变体，我们将采用一种减去性/添加剂策略，在该策略中，突触和认知表型将逐渐较小的基因组段链接到最小的关键临界区域，以逐步链接到逐渐较小的基因组细分。这项工作将为这些表型的最小关键区域内的病因基因奠定基础，这将为揭示与DS相关的认知障碍的分子机制奠定阶段，并为上述假设提供了决定性支持。因此，通过这些研究，我们期望在理解和治疗DS中的认知障碍方面有很大的加速。 公共卫生相关性：认知功能障碍基本上影响所有患有21三体疾病的儿童和成人，唐氏综合症（DS）；由于没有有效的治疗，美国有40万人在衰老期间与阿尔茨海默氏病神经病理学相关的认知能力的逐渐下降，因此有40万人的心理功能延迟。迫切需要采用创新的方法来阐明潜在的机制和开发有效的疗法。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的认知相关表型与最小关键基因组区域之间的联系，并最终的目标是确定鉴定原因的成就，这一成就将大大加快DS中认知和处理认知功能的进步。