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