UCSD Activities: Cooperative Efforts to Build a Shared Infrastructure Facilitating Biomedical Research Using Preclinical Mouse Models of Neurodegenerative Diseases

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UCSD Activities Cooperative Efforts to Build a
Shared Infrastructure Facilitating Biomedical
Research Using Preclinical Mouse Models of
Neurodegenerative Diseases

• Mark Ellisman, Ph.D., University of California
  San Diego

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UCSD Core 1 Data Acquisition

• Parkinsons Synuclein (alpha-syn) Transgenic
  Mouse Model
• Uploading and integrating behavioral and
  biochemical data into SRB.
• Preparing to submit manuscripts mGluR and
  dopamineR and will publish data through the BIRN
  federation of databases.
• Other Animal Models
• DAT KO Mouse UCSD will finish light and electron
  microscopy data analysis and write up the results
  for publication. All data will be made available
  through the BIRN federation of databases.
• EAE and Alzheimers model Waiting on material.

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Parkinsons Disease Mouse Animal Model Building
a BIRN multi-site, multi-disciplinary,
multi-agency collaboration

• NCMIR UCSD
• (M.H. Ellisman)
• Advanced light and
• electron microscopy
• Diana Price
• Van Phung
• Maryann Martone
• Heather Nguyen
• Andrea Thor

• Experimental Neuropathology Laboratory -UCSD (E.
  Masliah)
• Animal models Parkinsons strategy
• Edward Rockenstein
• Mike Mante

Additional collaborators Harvard University J.
Neumeyer Orally active apomorphine UICUC J.
George Targeted nanoparticle delivery of small
molecule therapeutics

• Duke University Center for In Vivo Micro
• (G.A. Johnson)
• Microscopic MRI
• Anjum Ali
• Mike Fehnel
• Sally Gewalt

Supported by The Branfman Family Foundation, NIH
(NCRR, NIDA, NIA) and MJ Fox Foundation.
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How well does the alpha-synclein mouse recreate
features of Parkinsons Disease?

• Widespread ?-synclein aggregates in CNS
• Neurochemistry
• mGluR5 receptor expression
• Dopamine D1/D2 receptors
• MRI studies volume composition
• Cognitive and motor deficits

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Multimodal studies of PD animal models
Behavior Assessment of cognitive and motor
function
Chemistry Genetics Protein expression Analyses
using Web QTL Ligand binding studies
Imaging Correlation of large-scale mapping of
immunolabeling and MRI studies Ultrastructural
studies using EM
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Alpha-synuclein Project Progress What we did
2005-present

• Continued progress towards the original project
  goals. Major highlights include
• September 2005 A large scale MRI imaging study,
  with improved resolution and contrast, was
  conducted and conjunction with Duke-CIVM
  researchers. These data are being processed and
  analyzed using methods and tools developed as
  part of the BIRN project.
• Throughout 2005 Continued characterization of
  neurotransmitter receptor distributions, which
  revealed significant alterations in mGluR5 and
  dopamine D1/D2 receptor immunoreactivity in
  alpha-synuclein transgenic animals CNS regions
  compared with non-transgenic control animals.
• Ongoing progress Continued integration of
  large-scale image and MRI data into BIRN
  databases and development of data mediation
  tools, which allow us to search for and analyze
  project data in distributed databases (ex.
  confocal images in CCDB and MRI volumes at Duke).
  
• Continued development Disease process maps and
  ontologies specific to Parkinsons disease
• July 2005 New partnerships and communication
  with other Parkinsons disease researchers,
  particularly relevant to the molecular mechanisms
  of alpha-synuclein aggregation and to symptomatic
  treatment of patients using new compounds.
• January 2006- Manuscript published Describes
  the mosaic image producing technique used to
  examine molecules related to Parkinsons Disease.
  
• Price DL, et al., 2006. High-Resolution
  Large-Scale Mosaic Imaging using Multiphoton
  Microscopy to Characterize Transgenic Mouse
  Models of Human Neurological Disorders.
  Neuroinformatics 4(1)65-80.

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Alpha-synuclein Project What UCSD will do
next

• Our goals for the next project period include
  (with targeted date for progress/completion)
• June 1, 2006 Submit mGluR5-related manuscript.
• June 15, 2006 Generate renewal application for
  support of work with Parkinsons collaborators -
  (Branfman Foundation).
• July 1, 2006 Generate average atlas from T1
  weighted MRI volumes.
• August 1, 1006 Complete segmentation of average
  atlas.
• August 15, 2006 Warp segmentations from average
  atlas back to original MRI volumes.
• September 1, 2006 Complete segmentation edits.
• September 15, 2006 Complete all analyses, draft
  manuscript outline.

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UCSD Core 2 Atlasing

• Continue to populate the database with
  multi-scale confocal and 2D and 3D EM data
  collected for Mouse BIRN for display in MBAT.
• Assist in the development of MBAT by advising
  regarding how to integrate the current
  functionality of the Smart Atlas for gene
  distribution query.
• Ensure that terminology is mapped to
  appropriate ontologies by MBAT developers.
• Work with Memphis (Williams) to map anatomical
  regions from microarray data to the MBAT atlas
  and the BIRN federation of databases.
• Work with BIRN CC and rest of atlasing group on
  the development/implementation of XML
  specification for spatial exchange of data
  between atlases.
• Register GENSAT and other gene expression data
  of relevance to the Mouse BIRN for distribution
  through MBAT and the BIRN federation of databases.

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BIRN Data Integration An example of federation
of Multi-scale, Multi-modal data from
Mouse BIRN
1. Create databases at each site
4. Use integration engine Mediator to navigate
and query across data sources
2. Create conceptual links to a shared ONTOLOGY
3. Situate the data in a common spatial
framework
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UCSD Core 3 Data Integration Progress over
past year

• Redesigned CCDB search and display pages to
  enhance usability and interoperability
• Removed account requirement
• Created a set of web services so that remote
  applications like MBAT can call the CCDB
• Created a set of Gridsphere portlets for data
  entry into the CCDB
• Created Gridsphere porlets for data upload and
  download to the BIRN data grid
• Worked with data integration group on the Mouse
  BIRN Global conceptual schema
• Mapped all of CCDB to Bonfire and provided source
  term index to the data integration team
• Created BIRNLex a simplified lexicon to aid
  in data mapping
• Created ontology for subcellular anatomy of the
  nervous system
• Created initial document defining the user
  scenario for Mouse BIRN Atlas tool