TECHNOLOGIES AND STRATEGIES FOR STUDYING GENE EXPRESSION CHANGES INPSYCHIATRIC DISEASE

association studies has strongly implicated multiple genetic influences in the

etiology of many mental illnesses.  Bipolar disorder, major depression,

schizophrenia and autism fall into this category, are likely to respond to new

treatment regimens, and present continuing, unmet medical needs.  One new

approach to understanding the biochemical underpinnings of these disorders

exploits the power of microarray technologies that measure the mRNA expression

of many genes in human brain and human neurons.  This contrasts with the

traditional approach of pursuing a single target for a given disease treatment,

or which search for incremental improvements on an existing target. Our

tripartite approach will be illustrated by experimental findings with (1) a

massively parallel, high throughput microarray platform to discover disease gene

changes in discrete regions of human brain, and analyzes cultured human neurons

and in vivo rat model systems in response to therapeutically effective

drugs. (2) Bioinformatic algorithms that identify gene groups and their

biochemical pathways involved in disease susceptibility and drug action. 

The resulting ‘gene signature’ forms the basis for multi-parameter throughput

screening (MPHTS^SM).  (3) Using small molecular compounds from

diverse libraries, MPHTS^SM is used to identify and optimize drug

candidates for further development.  Together, this information from human

gene signatures, drug signatures, and MPHTS^SM provides families of

new targets that will enable the discovery of therapeutics for each psychiatric

disease.  Changes in mRNA expression associated with schizophrenia and

bipolar disorder, and mRNA alterations in rodents and cultured human neurons

challenged with the antibipolar medication valproic acid, will be discussed in