Epilepsy is a devastating condition affecting over 50 million people worldwide. This multidisciplinary project is focused on the process leading to epilepsy, epileptogenesis, in adults. Our main hypothesis is that there are combinations of various causes, acting in parallel and/or in succession, that lead to epileptogenesis and development of seizures. Our central premise and vision is that a combinatorial approach is necessary to identify appropriate biomarkers and develop effective antiepileptogenic therapeutics. The project will focus on identifying novel biomarkers and their combinations for epileptogenesis after potentially epileptogenic brain insults in clinically relevant animal models, such as traumatic brain injury (TBI) and status epilepticus (SE); explore multiple basic mechanisms of epileptogenesis and their mutual interactions related to cell degeneration, circuit reorganization, inflammatory processes, free radical formation, altered neurogenesis, BBB dysfunction, genetic and epigenetic alterations; and translating these findings towards the clinic by validating biomarkers identified from animal models in human post TBI brain tissue and blood samples, post-mortem brain tissue in individuals that died soon after SE, and human brain and blood samples from chronic epilepsy cases. The project will identify novel combinatorial biomarkers and novel disease-modifying combinatorial treatment strategies for epileptogenesis, create an Epilepsy Preclinical Biobank, and validate translational potential of results from animal models in human tissue. To adequately address the proposed goals, the project will develop technological breakthroughs, such as completely novel chemogenetic approaches, novel MRI techniques, novel multimodal organic recording devices for simultaneous recordings of EEG / cellular unit activity and biochemical measurements, novel bioluminescence for in vivo promoter activity analysis, and novel systems biology approaches.