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: 8059586
• 负责人: KATHELEEN GARDINER
• 金额: $ 51.3万
• 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/8059586
• 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; Health; 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; 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（申请人提供）：唐氏综合症（DS）的发病率为七百分之一，目前预期寿命>50岁，平均智商约为50。因此，唐氏综合症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，都是在出生后出现的，这表明有效的治疗方法可能是可行的。 DS 是由于人类 21 号染色体 (chr21) 的额外拷贝及其编码的基因表达增加所致。 Chr21 基因影响多种途径； chr21 基因之间的通路和功能相互作用之间存在串扰。为了解决追求治疗目标的这些复杂性，我们提出了一种系统方法：（1）假设驱动：基于chr21蛋白的功能和我们对小鼠模型的行为/分子分析，我们假设DS中的认知缺陷是由MAPK、PI3K和钙调磷酸酶通路以及NMDA和GABAA受体（NMDAR， GABRA）功能。我们将偏向于特定途径成分的检测。 (2) 发现驱动：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 到 100 个样品和靶标中的额外扰动。 (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。该提案的目标是检验我们的假设，通过识别和预测其他关键通路扰动来制定新假设，并确定潜在的治疗靶点。为了实现这些目标，我们提出以下具体目标： 1. 定义候选路径中的基本扰动。基础基因型特异性分子谱将包括对五种 DS 小鼠模型的海马体、皮质和小脑的核、细胞质和膜部分进行的 48 种蛋白质测量。 2. 通过暴露于情境恐惧调节和 NMDAR 和 GABRA 拮抗剂治疗进行行为和药理学刺激后，在相同模型的相同途径中定义扰动。基因型/刺激特异性分子谱将与行为相关。 3. 在归纳机器学习和神经网络的支持下，使用模糊认知图描述关键路径特征并预测新扰动的结果。数据和通路将发布到我们的 Chr21 基因功能/通路数据库，http://chr21db.cudenver.edu。公共卫生相关性 唐氏综合症 (DS) 的发病率为七百分之一，目前预期寿命超过 50 岁，平均智商约为 50，这使得唐氏综合症成为一个重大的社会和医学问题。 DS 的许多表型特征，包括认知缺陷和神经解剖学异常，都是在出生后出现的，这表明有效的治疗方法可能是可行的。该应用程序将小鼠行为、药理学和分子分析与计算模型结合起来。目标是确定对学习和记忆至关重要的通路中的关键异常，并确定开发潜在疗法的有效靶点。