AWARD NUMBER: W81XWH-10-1-0380 TITLE: EPILEPSY AND THE WNT SIGNALING PATHWAY PRINCIPAL INVESTIGATOR: Dr. James DeGregori CONTRACTING ORGANIZATION: UNIVERSITY OF COLORADO DENVER

s: American Epilepsy Society Meeting 2011, 2012, 2013. Funding applied: DOD grants, CURE foundation grants (not funded). Successful funding of CURE foundation dream team grant on Infantile Spasms: Some preliminary data went into a successful multi-investigator CURE foundation grant on infantile spasms. Our discovery of Wnt signaling increases in epileptogenesis set the stage for the new research project. The team is Prof. Chris Dulla, Amy Yee, and Chris Dulla (PI). Dr. Audrey Yee had a key early role. Dr. Audrey Yee correctly identified Aicard’s like syndromes in a cAPCKO mice, predicted to have elevated Wnt signaling (owned by Dr. Michele Jacob). Drs. Amy Yee, Dulla and Jacob worked as a team to develop the project and investigate APC and Wnt signaling as an etiology for IS. Dr. Amy Yee created an elegant Infantile and Wnt signaling framework on which to evaluate and develop the multidisciplinary results. The working hypothesis incorporated the genetics of IS and numerous concepts of Wnt signaling gleaned from the cancer and developmental biology field. Remarkably, Dr. Yee noticed that several genes genetically linked to IS were directly linked to different aspects of Wnt pathway function, leading us to hypothesize that interference with Wnt signaling functions may be an excellent therapeutic strategy. Dr. Chris Dulla is analyzing the in vitro electrophysiology and in vivo EEG underlying the development of infantile spasms in the cAPCKO mice. CONCLUSION. These studies establish Wnt signaling and its metabolic network as a new set of molecular and therapeutic targets for the etiology of SE and potentially for epilepsy. The scientific discoveries underscore the importance of this expanded network and begin to advance the notion that the early period of epileptogenesis may recapitulate aspect s of brain development. The recapitulation to a period in earlier development has been a hallmark of diseases such as cancer. Our data would support models in the field in which epilepsy is a result of excessive stem cell proliferation and then abnormal differentiation—which together, set up a pathological environment that sustains seizures. Our observations that excessive glucose usage may contribute suggests that novel interventions such as the ketogenic diet may attenuating effects, Our studies also define a novel regiment of drugs in clinical uses that block Wnt signaling attenuates SE induced by two distinct means. These observations underscore the generality of Wnt signaling and provide proof-of-principle that intervening in Wnt signaling may be efficacious for modifying the course of epileptogenesis to prevent recurrent seizures. The Wnt pathway is under intense therapeutic development for cancer and other diseases. By defining the pre-clinical frameworks for epilepsy, this provides an ideal future opportunity to test drugs that attenuate Wnt signaling for their efficacy in disease modification for epilepsy.