Title: Pritzker Severe Mental Illness Research Consortium
1Pritzker 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.
2Questionhow Do We Study Brain Physiology,
Molecular Biology, Drug Development and Illness,
Now?
- Answer A Few Genes at a Time--if You Are Lucky!
3(No Transcript)
4What 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!!
5How Can These Enormous Barriers Be Overcome?
- A three-way alliance
- Neuroscience
- Molecular biology--human genome project
- High tech optics, electronic, mechanics,
computers and bioinfomatics
6General 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.
7Why 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.
8DNA Makes RNA makes Protein
- Two gene copies
- Hundreds to thousands of mRNA copiesThe Key
- Protein is the active agent of the genome
9How 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
10Specific 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.
11Major 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
-
12Flow of Studies and Relationship between Aspects
of the Project Sites Scientists Array Analysis
13Flow of Studies and Relationship between Aspects
of the Project Sites Scientists Post-array
Analysis
14Celera!!
15(No Transcript)
16Teleconferencing 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
17Aim 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.
18Brain 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.
19Donor 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
20UCI Brain Totals By Year
21(No Transcript)
22Thousands of mRNA types in each brain area!!!