Pritzker Severe Mental Illness Research Consortium

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Pritzker Severe Mental Illness Research Consortium

• Focused on Depression and Schizophrenia
• Sites and Senior Scientists
• U. of California at Irvine Davis
• Bunney and Jones
• Stanford University
• Cox and Schatzberg
• University of Michigan
• Akil and Watson.

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Questionhow Do We Study Brain Physiology,
Molecular Biology, Drug Development and Illness,
Now?

• Answer A Few Genes at a Time--if You Are Lucky!

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What Is the Size of the Brain Problem?

• Many brain regions --hundreds
• Many neuronal circuits--thousands
• Many and multiple neurotransmitters
• Over 100K genes 50 expressed in brain
• Both development and history are critical

So the brain is a Genetic Machine, of enormous
complexity and regulatory capacity--- and it
learns!!
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How Can These Enormous Barriers Be Overcome?

• A three-way alliance
• Neuroscience
• Molecular biology--human genome project
• High tech optics, electronic, mechanics,
  computers and bioinfomatics

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General Goals of Consortium

• Use modern genetic and neurobiological techniques
  to understand the biological basis of depression
  and schizophrenia.
• Identify genes and brain circuits which play a
  key role in the vulnerability to and expression
  of depression, schizophrenia and related
  illnesses.
• Use this information to establish novel
  strategies for the treatment and the prevention
  of these disorders.

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Why Use this Approach?

• Complex Genetic Nature of these Disorders.
  Searching for a Single Gene has Proven Useless.
  Need to Find Patterns of Genes.
• Role of Environment and Development not only in
  Triggering these Illnesses but in Modifying the
  Brain, thereby Increasing the Chance of
  Occurrence and Recurrence.
• Availability of Neurobiological Information to
  Guide Selection of Brain Sites to be Studied.

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DNA Makes RNA makes Protein

• Two gene copies
• Hundreds to thousands of mRNA copiesThe Key
• Protein is the active agent of the genome

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How Will We Actually Use These Genomics Tools?

• For mRNA levels by the thousands from a single
  tissues sampleMICROARRAYS! Or Other Expression
  Systems
• For The Study of Genetic Variation High
  Through-put Sequencing or Special Gene Arrays

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Specific Scientific Aims of the Consortium

• To Characterize Altered Profiles of Gene
  Expression in Specific Brain Circuits of
  Depressed, Schizophrenia and Control Individuals.
  
• Use Microarrays and other Methods to Study these
  Profiles in Postmortem Human Brains.
• To Ascertain Possible Differences in Genomic
  Structure in Selected Differentially Expressed
  Genes via Family Studies.
• To Understand the Expression, Distribution and
  Function of those Genes which Exhibit Significant
  Differences in Structure or Gene Expression.

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Major Components

• Aim I
• Postmortem Brains
• Microarray and Invader Assay Logic, Strategies,
  Techniques
• Follow-up on Differentially Expressed Genes
• Aim II
• Family Studies of Candidate Genes
• Aim III
• Rodent Studies
• Primate Studies

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Flow of Studies and Relationship between Aspects
of the Project Sites Scientists Array Analysis
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Flow of Studies and Relationship between Aspects
of the Project Sites Scientists Post-array
Analysis
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Celera!!
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Teleconferencing Tools

• All 4 Sites Contacted ( 2 Systems at Stanford
  n5)
• Phone Conferencing -- Better than Web
• NetMeeting Via Web For Data Sharing- Any
  Application For All to See and Edit
• One-to-Many
• Video Projector For Many Participants

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Aim I Post-Mortem Studies

• Postmortem Brains Acquisition and
  Characteristics.
• Microarray and Invader Assay Logic, Strategies,
  and Technical Considerations.
• In Situ Hybridization Validation of Differential
  Expression of Specific Genes Detected by
  Microarray.

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Brain Status to Date

• Chosen and dissected eight normal brains (4
  female and 4 male) for regional anatomical and
  array and invader assay calibration (250 blocks).
• Matched nine depressed and nine controls.
  Dissected and will be studied in the next few
  months (1,000 blocks).
• Several Schizophrenic and Depressed and Normals
  in Process.
• Tissue for Transplant Act and the Bunney/Jones
• Brain bank.

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Donor Referral and Consent Center

• Newly formed regional center that takes all
  hospital deaths in Orange, Los Angeles and
  various northern counties
• Psychiatric screening questions for all reported
  deaths initially for Orange County with eventual
  expansion into L.A.
• Orange County reports 1800 annually
• L.A.County approximately 5000 annually

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UCI Brain Totals By Year
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Thousands of mRNA types in each brain area!!!