Systems Biology for Studies of Cognition in Down Syndrome

唐氏综合症认知研究的系统生物学

• 批准号: 7797677
• 负责人: KATHELEEN GARDINER
• 金额: $ 51.86万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797677
• 关键词: 1 year old; 1-Phosphatidylinositol 3-Kinase; Acute; Address; Aftercare; Amyloid beta-Protein Precursor; Antibodies; Behavior; Behavior Control; Behavioral; Biological Assay; Biological Neural Networks; Calcineurin; Calcineurin Pathway; Calcineurin inhibitor; Cell membrane; Cerebellum; Characteristics; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 21; Chronic; Cognition; Cognitive; Cognitive deficits; Complex; Computer Simulation; Critical Pathways; Data; Databases; Development; Down Syndrome; Exposure to; Gene Expression; Generations; Genes; Genetic; Genotype; Goals; Guanine Nucleotide Exchange Factors; Hippocampus (Brain); Human Chromosomes; Incidence; Individual; Infant; Learning; Life Expectancy; Live Birth; MAP Kinase Gene; MK801; Machine Learning; Maps; Measurement; Measures; Medical; Memantine; Memory; Memory impairment; Methodology; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Analysis; Molecular Biology; Molecular Profiling; Mus; Mutate; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neural Network Simulation; Nuclear; Outcome; Output; Pathway interactions; Pentylenetetrazole; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Phase; Phosphoric Monoester Hydrolases; Phosphorylation; Population; Predictive Value; Protein Array; Protein Kinase; Proteins; Publishing; Research Personnel; Resources; Sampling; Set protein; Signal Pathway; Signal Transduction; Solutions; System; Systems Biology; Task Performances; Testing; Therapeutic; Therapeutic Intervention; Transgenic Organisms; Trisomy; United States; Validation; aged; arm; base; brain tissue; conditioned fear; design; familial Alzheimer disease; gene function; intersectin 1; male; mathematical model; mouse Ts1Cje; mouse Ts65Dn; mouse model; multidisciplinary; network models; novel; overexpression; postnatal; public health relevance; rac GTP-Binding Proteins; receptor; response; social; synaptojanin; therapeutic target; therapy design; time interval

DESCRIPTION (provided by applicant): The incidence of Down syndrome (DS) is one in 700 live births, the life expectancy is now >50 years, and the average IQ is approximately 50. Therefore, DS is a significant social and medical issue. Many phenotypic features of DS, including cognitive deficits and neuroanatomical abnormalities, develop postnatally, arguing that effective therapeutics may be feasible. DS is due to an extra copy of human chromosome 21 (chr21) and the increased expression of genes encoded by it. Chr21 genes impact multiple pathways; there is cross talk among the pathways and functional interactions among chr21 genes. To address these complexities in pursuit of therapeutic targets, we propose a systems approach that is: (1) Hypothesis driven: Based on the functions of chr21 proteins and our behavioral/ molecular analysis of mouse models, we hypothesize that the cognitive deficits in DS are caused by perturbations in MAPK, PI3K and calcineurin pathways and NMDA and GABAA receptor (NMDAR, GABRA) function. We will bias our assays towards specific pathway components. (2) Discovery driven: in a less biased screen, we will use Reverse Phase and antibody arrays to assay for additional perturbations in 10s to 100s of samples and targets. (3) Multidisciplinary: The PI and co-PIs provide expertise in molecular biology, mouse behavioral and pharmacological analysis, and mathematical modeling. The goals of this proposal are to test our hypothesis, to develop new hypotheses by identifying and predicting additional critical pathway perturbations, and to identify potential targets for therapeutics. To fulfill these goals, we propose the following specific aims: 1. Define basal perturbations in candidate pathways. Basal genotype-specific molecular profiles will include 48 protein measurements made in nuclear, cytoplasmic and membrane fractions, from hippocampus, cortex and cerebellum, from five DS mouse models. 2. Define perturbations, in the same pathways in the same models, after behavioral and pharmacological stimulation by exposure to Contextual Fear Conditioning and treatment with NMDAR and GABRA antagonists. Genotype/stimulation-specific molecular profiles will be correlated with behavior. 3. Describe key pathway features and predict results of novel perturbations using Fuzzy Cognitive Maps, supported by Inductive Machine Learning and Neural Networks. Data and pathways will be posted to our Chr21 Gene Function/Pathway database, http://chr21db.cudenver.edu. PUBLIC HEALTH RELEVANCE The incidence of Down syndrome (DS) is one in 700 live births, the life expectancy is now >50 years, and the average IQ is approximately 50, making DS is a significant social and medical issue. Many phenotypic features of DS, including cognitive deficits and neuroanatomical abnormalities, develop postnatally, arguing that effective therapeutics may be feasible. This application combines mouse behavior, pharmacology and molecular analyses with computational modeling. The goal is to define key abnormalities in pathways critical for learning and memory and to identify effective targets for development of potential therapeutics.

描述（由申请人提供）：唐氏综合征（DS）的发病率为700例活产婴儿中的1例，目前预期寿命>50岁，平均智商约为50。因此，DS是一个重要的社会和医学问题。DS的许多表型特征，包括认知缺陷和神经解剖学异常，在出生后发展，认为有效的治疗方法可能是可行的。DS是由于人类21号染色体（chr 21）的额外拷贝及其编码的基因表达增加。chr 21基因影响多个通路;通路之间存在串扰，chr 21基因之间存在功能相互作用。为了解决这些复杂性，在追求治疗目标，我们提出了一个系统的方法，即：（1）假设驱动：基于chr 21蛋白的功能和我们的行为/分子分析的小鼠模型，我们假设，在DS的认知缺陷是由MAPK，PI 3 K和钙调神经磷酸酶通路和NMDA和GABAA受体（NMDAR，GABRA）功能的扰动。我们将使我们的测定偏向于特定的通路组分。(2)探索驱动：在偏差较小的筛选中，我们将使用反相和抗体阵列来测定10秒至100秒的样品和靶中的额外扰动。(3)多学科：PI和co-PI提供分子生物学，小鼠行为和药理学分析以及数学建模方面的专业知识。该提案的目标是验证我们的假设，通过识别和预测其他关键途径扰动来开发新的假设，并确定潜在的治疗靶点。为实现这些目标，我们提出了以下具体目标：1。定义候选通路中的基础扰动。基础基因型特异性分子谱将包括在来自5种DS小鼠模型的海马、皮质和小脑的核、细胞质和膜组分中进行的48种蛋白质测量。2.通过暴露于情境性恐惧条件反射和使用NMDAR和GABRA拮抗剂治疗，在相同模型的相同通路中定义行为和药理学刺激后的扰动。基因型/刺激特异性分子谱将与行为相关。3.描述关键通路特征，并使用模糊认知图预测新扰动的结果，由归纳机器学习和神经网络支持。数据和途径将发布到我们的Chr 21基因功能/途径数据库，http://chr21db.cudenver.edu。唐氏综合症（Down syndrome，DS）的发病率是每700名活产婴儿中有1名，现在的预期寿命超过50岁，平均智商约为50，使DS成为一个重要的社会和医学问题。DS的许多表型特征，包括认知缺陷和神经解剖学异常，在出生后发展，认为有效的治疗方法可能是可行的。该应用程序结合了小鼠行为，药理学和分子分析与计算建模。其目标是确定对学习和记忆至关重要的途径中的关键异常，并确定开发潜在治疗方法的有效靶点。