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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD056235-05
Application #
8239531
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Oster-Granite, Mary Lou
Project Start
2008-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$515,296
Indirect Cost
$169,467
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Strack, Beata; DeShazo, Jonathan P; Gennings, Chris et al. (2014) Impact of HbA1c measurement on hospital readmission rates: analysis of 70,000 clinical database patient records. Biomed Res Int 2014:781670
Costa, Alberto C (2012) Alzheimer disease: Treatment of Alzheimer disease in Down syndrome. Nat Rev Neurol 8:182-4
Sturgeon, Xiaolu; Le, Thanh; Ahmed, Md Mahiuddin et al. (2012) Pathways to cognitive deficits in Down syndrome. Prog Brain Res 197:73-100
Ahmed, Md Mahiuddin; Sturgeon, Xiaolu; Ellison, Misoo et al. (2012) Loss of correlations among proteins in brains of the Ts65Dn mouse model of down syndrome. J Proteome Res 11:1251-63
Scott-McKean, Jonah J; Costa, Alberto C S (2011) Exaggerated NMDA mediated LTD in a mouse model of Down syndrome and pharmacological rescuing by memantine. Learn Mem 18:774-8
Costa, Alberto C S (2011) On the promise of pharmacotherapies targeted at cognitive and neurodegenerative components of Down syndrome. Dev Neurosci 33:414-27
Ahmed, Md Mahiuddin; Gardiner, Katheleen J (2011) Preserving protein profiles in tissue samples: differing outcomes with and without heat stabilization. J Neurosci Methods 196:99-106
Costa, Alberto C S (2011) An assessment of optokinetic nystagmus (OKN) in persons with Down syndrome. Exp Brain Res 214:381-91
Liu, Chunhong; Morishima, Masae; Yu, Tao et al. (2011) Genetic analysis of Down syndrome-associated heart defects in mice. Hum Genet 130:623-32
Nguyen, Cao D; Costa, Alberto C S; Cios, Krzysztof J et al. (2011) Machine learning methods predict locomotor response to MK-801 in mouse models of down syndrome. J Neurogenet 25:40-51

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