Systems Biology for Studies of Cognition in Down Syndrome

唐氏综合症认知研究的系统生物学

基本信息

批准号：
8066269
负责人：
KATHELEEN GARDINER
金额：
$ 9.99万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-10 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8066269
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

项目摘要

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）：唐氏综合症（DS）的发病率是700个活产，预期寿命> 50年，平均智商约为50年。因此，DS是一个重大的社会和医疗问题。 DS的许多表型特征，包括认知缺陷和神经解剖异常，在产后发展，认为有效的治疗剂可能是可行的。 DS是由于人类染色体21（CHR21）的额外副本以及由其编码的基因表达增加所致。 CHR21基因会影响多个途径。 CHR21基因之间的途径和功能相互作用之间存在串联。为了解决追求治疗靶标的这些复杂性，我们提出了一种系统方法：（1）驱动的假设：基于Chr21蛋白的功能以及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CACINERARIN和NMDA和NMDA和NMDA，NMDA和NMDA，GAB和NMDA引起的， gabra）功能。我们将使测定法偏向特定的途径组件。（2）发现驱动的：在较小的屏幕中，我们将使用反相和抗体阵列来测定10秒至100 s的样品和目标的其他扰动。（3）多学科：PI和CO-PI提供了分子生物学，小鼠行为和药理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途径扰动，并确定治疗剂的潜在靶标，从而提出新的假设。为了实现这些目标，我们提出以下特定目标：1。定义候选途径中的基础扰动。基础基因型特异性分子谱将包括来自五个DS小鼠模型的海马，皮层和小脑的48种核，细胞质和膜级分制的蛋白质测量值。 2。在相同模型中的相同途径中定义扰动，在行为和药理刺激后通过暴露于情境恐惧调节和使用NMDAR和GABRA拮抗剂治疗的情况下定义扰动。基因型/刺激特异性分子谱将与行为相关。 3。描述使用模糊的认知图，在电感机器学习和神经网络支持的情况下，使用模糊认知图来预测新型扰动的结果。数据和途径将发布到我们的CHR21基因函数/途径数据库，http://chr21db.cudenver.edu。公共卫生相关性唐氏综合症（DS）的发生率是700个活产的中断，预期寿命> 50年，平均智商约为50年，使DS成为一个重大的社会和医疗问题。 DS的许多表型特征，包括认知缺陷和神经解剖异常，在产后发展，认为有效的治疗剂可能是可行的。该应用结合了小鼠的行为，药理学和分子分析与计算建模。目的是定义对学习和记忆至关重要的途径中的关键异常，并确定有效的潜在治疗剂目标。