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.
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.
|Gupta, Meenal; Dhanasekaran, A Ranjitha; Gardiner, Katheleen J (2016) Mouse models of Down syndrome: gene content and consequences. Mamm Genome 27:538-555|
|Higuera, Clara; Gardiner, Katheleen J; Cios, Krzysztof J (2015) Self-Organizing Feature Maps Identify Proteins Critical to Learning in a Mouse Model of Down Syndrome. PLoS One 10:e0129126|
|Ahmed, Md Mahiuddin; Dhanasekaran, A Ranjitha; Block, Aaron et al. (2015) Protein dynamics associated with failed and rescued learning in the Ts65Dn mouse model of Down syndrome. PLoS One 10:e0119491|
|Gardiner, Katheleen J (2015) Pharmacological approaches to improving cognitive function in Down syndrome: current status and considerations. Drug Des Devel Ther 9:103-25|
|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|
|Sturgeon, Xiaolu H; Gardiner, Katheleen J (2012) RCDA: a highly sensitive and specific alternatively spliced transcript assembly tool featuring upstream consecutive exon structures. Genomics 100:357-62|
|Costa, Alberto C (2012) Alzheimer disease: Treatment of Alzheimer disease in Down syndrome. Nat Rev Neurol 8:182-4|
|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|
|Boada, R; Hutaff-Lee, C; Schrader, A et al. (2012) Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial. Transl Psychiatry 2:e141|
|Sturgeon, Xiaolu; Le, Thanh; Ahmed, Md Mahiuddin et al. (2012) Pathways to cognitive deficits in Down syndrome. Prog Brain Res 197:73-100|
Showing the most recent 10 out of 25 publications