The search for the genetic basis of neuropsychiatric disease is a major focus of current research in biologic psychiatry. Alterations in monoaminergic neurotransmission are thought to have a pathophysiologic role in many neuropsychiatric disorders. We intend to approach the study of the genetics of neuropsychiatric disease using a candidate gene approach, focusing on the potential role of constitutively activated monoaminergic neurotransmitter receptors. We intend to apply a novel phenotypic assay of receptor function, R-SAT (Receptor Selection and Amplification Technology), to screen patient populations for constitutively active monoaminergic receptors. R-SAT screening involves the high throughput PCR amplification and subcloning of receptor sequences from a patient's genomic DNA, coupled to their transient expression in mammalian cells for phenotypic analysis. Constitutively active receptors will be identified and the causative mutations will be determined by DNA sequencing. This data will enable us to conduct traditional population based genetic studies to assess, the prevalence and role of constitutively active receptors in neuropsychiatric disease. PROPOSED COMMERCIAL APPLICATIONS: The identification of a genetic cause of a major mental illness would create two significant commercial opportunities. 1) The creation of a diagnostic test for the disease in question, and 2) the knowledge necessary to design a specific, potentially curable, therapeutic agent for the disease in question.
