Mouse BIRNCORE 4: Applications

Mouse BIRNCORE 4: Applications

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1. Extend out from growing strengths in multi-modal multi-scale imaging of the mouse CNS to link up with numerous molecular and genetic resources. ADD LINKAGE to GENOMICS.

2. Provide a TRANSLATIONAL BRIDGE between mouse and human neurological disease that relies on common disease progression, shared behavior and phenotypes and MOLECULAR SIGNATURES.

3. VALIDATE models on two or more genetic backgrounds. What features are robust? What generalizes well between mouse and human populations?

1. Extend out from growing strengths in multi-modal multi-scale imaging of the mouse CNS to link up with numerous molecular and genetic resources. ADD LINKAGE to GENOMICS.

2. Provide a TRANSLATIONAL BRIDGE between mouse and human neurological disease that relies on common disease progression, shared behavior and phenotypes and MOLECULAR SIGNATURES.

3. VALIDATE models on two or more genetic backgrounds. What features are robust? What generalizes well between mouse and human populations?

Three models of neurodegenerationThree models of neurodegenerationMultiple sclerosis (Voskuhl, MOG EAE model) Multiple sclerosis (Voskuhl, MOG EAE model)

Alzheimer’s disease (Jankowsky, Human Tg line) Alzheimer’s disease (Jankowsky, Human Tg line)

Parkinson’s disease (Masliah, Human Tg line) Parkinson’s disease (Masliah, Human Tg line)

Three stages of progression + controlMales and femalesTwo fully sequenced strains (C57BL/6J and

DBA/2J)Three replicates (± 2)As many modalities as possible

Three stages of progression + controlMales and femalesTwo fully sequenced strains (C57BL/6J and

DBA/2J)Three replicates (± 2)As many modalities as possible

Diana PriceDiana Price

General Design

New Modality: mRNA expression levelNew Modality: mRNA expression level

~40,000 transcript assays Often use a split design (histo<–>array)Lumping vs splitting (whole brain)Will generate modulated transcript sets

Then what?

~40,000 transcript assays Often use a split design (histo<–>array)Lumping vs splitting (whole brain)Will generate modulated transcript sets

Then what?

Analysis of signature lists

Mediation with WebQTL

Analysis of signature lists

Mediation with WebQTL

Analysis of disease signature lists withAnalysis of disease signature lists with

What is the network connectivity of list members?

What are the mechanistic common denominators of lists?

Are there final common pathways?

How do we ensure high quality lists? (Partial answer: replicate on two genetic backgrounds)

What is the network connectivity of list members?

What are the mechanistic common denominators of lists?

Are there final common pathways?

How do we ensure high quality lists? (Partial answer: replicate on two genetic backgrounds)

Genetic CorrelationsGenetic Correlations

with Ken Manlywith Ken Manly

Group AVamp8Vamp5RapsnSyngr4Snap23Syt3Rnp24Sybl1Syt8Acv1Syt7Syt10Sycp1Syt5

Group AVamp8Vamp5RapsnSyngr4Snap23Syt3Rnp24Sybl1Syt8Acv1Syt7Syt10Sycp1Syt5

Group BSnpa91Synj2Sybl1Syt4Syt5VdpVti1bRnp24Vamp3Sec22l1Syn2Syn1VapaVamp1Syt11Vamp4Vamp1

Group BSnpa91Synj2Sybl1Syt4Syt5VdpVti1bRnp24Vamp3Sec22l1Syn2Syn1VapaVamp1Syt11Vamp4Vamp1

The Two Strains: C57BL/6J and DBA/2JThe Two Strains: C57BL/6J and DBA/2J

First two inbred strains made at TJL

Very extensive phenotype and CNS data

Disease susceptibility well characterized

1.8 million defined SNPs Large RI set

First two inbred strains made at TJL

Very extensive phenotype and CNS data

Disease susceptibility well characterized

1.8 million defined SNPs Large RI set

What are recombinant inbred strains (RI)What are recombinant inbred strains (RI)

C57BL/6J (B)C57BL/6J (B) DBA/2J (D)DBA/2J (D)

F1F1

20 generations

brother-sister

matings

20 generations

brother-sister

matings

BXD1BXD1 BXD2BXD2 BXD80BXD80+ … ++ … +

F2F2

BXD RIStrain setBXD RI

Strain set

fullyinbredfully

inbred

isogenicisogenic

hetero-geneoushetero-

geneous

Recombined chromosomes are

needed for mapping

Recombined chromosomes are

needed for mapping

femalefemale malemale

chromosome pairchromosome pair

InbredIsogenicsiblings

InbredIsogenicsiblings

BXDBXD

Mediation with the MBL Mediation with the MBL

with Glenn Rosen

Mouse Brain LibraryMouse Brain Library

Low-res serial Nissl stain for stereologyLow-res serial Nissl stain for stereology

Mediation with the iScopeMediation with the iScope

Clique analysis: Mike Langston, Elissa Chesler

CollaboratorsCollaborators

Ken ManlyJintao WangMichael LangstonMichele BaldwinGlenn Rosen

Ken ManlyJintao WangMichael LangstonMichele BaldwinGlenn Rosen

Lu Lu Elissa Chesler David Airey Jing Gu Shuhua Qi Hong Tao Zhang Arthur Centeno Yanhua Qu

Lu Lu Elissa Chesler David Airey Jing Gu Shuhua Qi Hong Tao Zhang Arthur Centeno Yanhua Qu

National Institute of Mental Health, National Institute on Drug Abuse, and the National Science Foundation (P20-MH 62009)

National Institute of Mental Health, National Institute on Drug Abuse, and the National Science Foundation (P20-MH 62009)