Sphingosine-1-phosphate 1 (S1P1) Receptor Signaling Mouse for Therapeutic Development

This technology includes a mouse model for studying SiP1 receptor signaling for development of therapeutics for a variety of conditions. The S1P1 receptor locus of the mouse has been modified by gene targeting to encode a fusion of the S1P1 receptor and the tetracycline-controlled activator protein (tTA) connected by a Tobacco Etch Virus (TEV) cleavage sequence, internal ribosome initiation sequence (IRES), followed by a beta-arrestin-Tobacco Etch Virus (TEV) protease fusion protein. When activated, the modified S1P1 receptor binds the beta-arrestin-TEV protease fusion, which cleaves the tTA. The released tTA activates a reporter gene under transcriptional control of a tetracyclineresponsive promoter element (TRE) thereby reporting S1P1 receptor activation. Since S1P1 receptor signaling may be important in diseases such as multiple sclerosis, cancer and atherosclerosis, the mouse can be used to identify active compounds that alter S1P1 receptor signaling and that may be therapeutically useful.