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2005 All Hands Meeting
Science of the
Mouse models of human neurodegenerative disease
Mouse BIRN Data Integration Framework
2. Create conceptual links to a shared ontology
1. Create multimodal databases
3. Situate the data in a common spatial framework
4. Use mediator to navigate and query across data sources
Mouse models of neurological disease
Allow us to better understand the disease mechanism and potential therapies of related human neurological disorders
• Use of single strain (essentially “clones”): Different imaging modalities Different ages or progression Gene manipulation: strain is it’s own control Different therapies
• Multiple strains and crossbreeding: Genetics and environment Therapeutic interactions
Mouse BIRN models
Parkinson’s Multiple Sclerosis Alzheimer’s
Parkinson’s Disease (-synuclein model)
Lewy Bodies
Alpha-synuclein protein (-SYN) aggregates
Found in several brain areas in PD
Mouse model overexpressing -SYN
• PD like pathology
• Motor deficits
Link expression of -SYN to behavior and structure
-synuclein Results slide
Assessment of cognitive and motor function
Genetic analyses
(Web QTL)
Ultrastructural studies using
EM
Correlation of large-scale mapping of immunolabeling
and MRI studies
Multiple Sclerosis (EAE model)
Inflammatory autoimmune demyelinating diseases• Demyelination and axonal degeneration• Limb weakness and paralysis
Experimental Autoimmune Encephalomyelitis (EAE): • Induced inflammatory autoimmune disease• Chronic progressive disability • Differential susceptibility across strains and antigens
Examine disease progression and severity in relation to structure
EAE Results slide
Alzheimer’s Disease
Several mouse models over-express APP (A precursor protein)
These accumulate amyloid- (A) protein• Aggregates into extracellular lesions (amyloid plaques) • Found throughout the hippocampus and cortex• Accumulation of plaques similar to human
New collaborator’s model: turn on/off mutant APP production• Examine if there is recovery• Time course of recovery
Great place for integration with Morph testbed
Situate data in a common spatial framework
Image ProcessingRegistration
Reconstruction
Coregistered Data
Designing this Framework
BAMS
WebQTL
Spatially Coregistered Images in Database
Coregistered Atlas Modules
Web Based Resources
Ontologies
MOUSE BIRN VIEWING TOOL
Multiple Ways of Querying Data
Brain
Cerebellum
Purkinje Cell Layer
Purkinje cell
neuron
has a
has a
has a
is a
Spatial (Atlases)
Transformations
Ontologies
Progress on interoperative atlasing interface
SmartAtlas
SHIVA
Neuroterrain
Individual Mouse BIRN Atlas Tools Mouse BIRN Integrated Tool
Mouse Orientation and Registration Tool
(MORT)
In the last year
Cyr M, Caron MG, Johnson GA, Laakso A, (2005) Magnetic resonance imaging at microscopic resolution reveals subtle morphological changes in a mouse model of dopaminergic hyperfunction, NeuroImage, 26:83-90
Anjum A. Ali, Anders M. Dale, Alexandra Badea, G. Allan Johnson (2005) Automated Segmentation of Neuroanatomical Structures in Multispectral MR Microscopy of the Mouse Brain. NeuroImage, 27:425-35
Price DL, Chow SK, MacLean NAB, Hakozaki H, Peltier S, Martone ME, Ellisman MH (In Press) High-Resolution Large-Scale Mosaic Imaging using Multiphoton Microscopy to Characterize Transgenic Mouse Models of Human Neurological Disorders. Neuroinformatics.
Erh-Fang L, Jacobs RE, Dinov I, Leow A, Toga A, (In Press) Standard Atlas Space for C57BL/6 Neonatal Mouse Brain. Anatomy and Embryology
MacKenzie-Graham A, Tinsley M, Shah KP, Aguilar C, Strickland LV, Boline J, Martin M, Morales L, Shattuck DW, Jacobs RE, Voskuhl RR, Toga AW, (In Progress) Cerebellar Cortical Atrophy in C57BL/6J Mice with Experimental Autoimmune Encephalomyelitis.
D.L. Price, E. Rockenstein, N.A.B. MacLean, M. Mante, V. Phung, D. Askay, E. Masliah, and M.H. Ellisman (In preparation) Increased mGluR5 immunoreactivity and behavioral deficits in transgenic mice overexpressing alpha-synuclein
PUBLICATIONS IN PRESS IN PREPARATION
Summary
Create powerful intuitive infrastructure to incorporate, visualize, manage, search, analyze, and compare data
Use these tools to help characterize mouse models of neurodegenerative disease, with the goal of better understanding the disease mechanism and potential therapies
Share these technologies with the scientific community