NOVEL VALIDATION TECHNOLOGIES FOR PSYCHIATRIC DISEASE

DESCRIPTION (provided by applicant): This proposal is being sent in response to NIMH Program Announcement #PA-02-027 entitled." Pharmacologic Agents and Drugs for Mental Disorders (SBIR Award)."The nervous system presents special challenges to the high-throughput validation of potential targets and optimization of small molecule lead compounds during psychiatric drug development Current approaches to target validation to a large degree involve the generation of hypothesis-specific transgenic animals on a target-by-target basis useful for testing the involvement of a particular protein in a biological process Such animal models are expensive and time consuming to construct and analyze, especially if multiple targets are in need of validation Furthermore, assaying changes in neuronal activity of specific neurons in vitro in response to genetic or chemical perturbations would likely be a first method of choice for both target validation and lead optimization However, the heterogeneity of the nervous system, the absence of identifying characteristics for relevant neurons, and the often small number of those relevant neurons in any particular brain region, currently preclude the facile identification of the relevant neurons for such electrophysiological measurements. Because our goal is the discovery of new drugs for mental disorders, we propose in this SBIR Fast-Track application (Phase I portion) to establish the feasibility of building a novel technology platform that overcomes these obstacles and permits higher-throughput target validation and lead optimization during psychiatric drug discovery than is currently available In this platform, we will create a collection of transgenic mouse lines that will (1) permit genetic perturbations of neuronal function for the validation of an unlimited number of targets in specified neuronal subclasses (or for the validation of the role of these subclasses themselves in an indication), and (2) permit the facile identification of these neurons in vitro, enabling measurements of their electrophysiology during target validation and lead optimization.