Behavioral disorders, while rarely fatal, can be very disruptive to normal life and exist among adults at a substantial prevalence. According in the Surgeon General's report released in 1999, an estimated that 58 million Americans or approximately 1 in 5 individuals will experience a mental disorder in the course of a year. Many regions of the brain have been implicated in the control of behavior; however, the limbic system has been most closely linked to emotional behaviors including anxiety. G-protein-coupled receptors (GPCR) belong to a large family of proteins that have historically proven to form a valuable group of targets for development of drugs. Brain is especially abundant in this class of receptors, but functions of the majority of them are not known. We believe that many receptors, especially those that are expressed in limbic system, are involved in control of basic behavioral functions and should provide valuable targets for drugs to treat behavioral disorders including anxiety disorders. Identification of the function of the specific genes with respect to behavior will allow discovery of new drugs that can be used to modify behavior. The close similarity between the mouse and human genes and functional and anatomical conservation of the areas of the brain that are the focus of our interest make the mouse a good model for identification of genes that will be of value in the discovery of useful drugs for treatment of humans. Phase I will determine which orphan non-sensory GPCRs have brain expression profiles that correlate with the areas of the brain known to be important in control of anxiety. Using an innovative retroviral vector and high throughput gene knockout technology, prepare embryonic stem (ES) cells inactive in each of the respective genes. These ES cells will be used in Phase II to make knockout mice and investigate the relationship of the specific genes to specific behaviors related to anxiety. The genes and eventually, the proteins they code for may be useful drug targets for discovery of new drugs to treat the disruptive behavioral disorders.
| Gragerov, Alexander; Horie, Kyoji; Pavlova, Maria et al. (2007) Large-scale, saturating insertional mutagenesis of the mouse genome. Proc Natl Acad Sci U S A 104:14406-11 |
| Zeng, Hongkui; Gragerov, Alexander; Hohmann, John G et al. (2006) Neuromedin U receptor 2-deficient mice display differential responses in sensory perception, stress, and feeding. Mol Cell Biol 26:9352-63 |
