Candidate: Dr. Robert Kotloski is a staff neurologist in the Epilepsy Center of Excellence and in the Traumatic Brain Injury/Polytrauma (TBI) clinics at the William S. Middleton Memorial Veterans Hospital. He is also a research fellow and instructor in the Department of Neurology at the University of Wisconsin. Dr. Kotloski has completed a combined MD/PhD degree at Duke University School of Medicine, during which time he studied molecular mechanisms of epileptogenesis. He has completed a residency in Neurology at Wake Forest University and a Clinical Neurophysiology fellowship with an epilepsy focus at the University of Wisconsin. He is applying for a VA CDA-2 award in order to obtain the career development training and support for scientific study to become an independent VA researcher. Environment: Dr. Kotloski will complete the proposed research at the VA and the University of Wisconsin. Both organizations provide an exceptionally collegial atmosphere and strong institutional support including protected time, research space, and equipment. The unique strains of in-bred rats are only available through the laboratory of a mentor, Dr. Thomas Sutula, and have not been used for TBI research previously. Career Plan: Dr. Kotloski's long-term career goals include the establishment of an independent, productive research laboratory focused on understanding TBI, post-traumatic epilepsy (PTE), and its comorbidities. Through his mentors, he will enhance his knowledge of animal models of epilepsy and TBI including cellular (Dr. Rutecki) and network (Dr. Sutula) mechanisms of epilepsy, and molecular mechanisms of TBI (Dr. Vemuganti). During the course of this proposal, he will hone his skills in manuscript and grant writing, mentoring, presentation, and laboratory management. Dr. Kotloski expects the proposed research and training will allow him to independently compete for VA Merit Review funding prior to the end of the CDA-2 award. Research Project: Current understanding of devastating residuals of TBI such as epilepsy is limited by a paucity of useful animal models. However a unique, plasticity-susceptible strain of rat, selected for increased rate of kindling, has demonstrated frequent post-traumatic seizures following moderate-to-severe TBI. The immediate goal of this proposal is to test the hypothesis that, following a traumatic brain injury, the development of epilepsy is preceded by changes in electrophysiologic activity and protein expression which are predictive of the later occurrence of PTE.
Aim 1 is to characterize spontaneous electrographic changes and post-traumatic seizures after TBI in unique rat strains and out-bred rats. Two complementary strains of in-bred rats, one selected for increased rate of kindling (plasticity-susceptible) and another selected for decreased rate of kindling (plasticity-resistant), as well as out-bred Sprague-Dawley rats, will be studied. TBI will be induced by controlled cortical impact (CCI) and electrophysiologic activity will be recorded from the time of injury through the development of PTE. The goal of this aim is to identify changes in electrophysiologic activity following TBI and prior to the appearance of seizures, which would advance our understanding of this critical but clinically silent period, and which could serve as biomarkers for post-traumatic epileptogenesis.
Aim 2 is to examine the molecular mechanisms underlying post-traumatic epileptogenesis. Protein expression patterns from the brains of rats from the three genetic backgrounds at various time points following the CCI will be correlated to the presence or absence of PTE. Molecules known to be involved in the response to TBI and in epileptogenesis, including BDNF, TrkB, Tau, A?, and GFAP, will be studied. The goal of this aim is to identify molecular mechanisms and brain structures underlying the development of PTE, which could guide the development of potential therapeutics. As TBI and PTE impact a significant number of Veterans and civilians, and current diagnostic and therapeutic options are severely limited, improved understanding of this prevalent and challenging disorder will greatly advance our ability to care for these individuals.
Post-traumatic epilepsy (PTE) is a major health problem within the VA. In 2011, 87,377 Veterans had epilepsy, of whom 15.8% had co-morbid traumatic brain injury (TBI). Due to combat exposures, an even greater proportion (52.6%) of OEF/OIF/OND Veterans with epilepsy also had TBI, at 3 times the rate in civilian populations, underscoring the present and continuing importance of PTE to the VA. A period of years is often present between the TBI and the first seizure of PTE, during which a slowly evolving process induces permanent changes in the brain (epileptogenesis). Currently we are unavailable to detect epileptogenesis during this critical but clinically silent period, and no treatments are available. The goal of this project is to utilize a novel animal model of PTE to identify electrographic biomarkers of epileptogenesis, leading to improved diagnosis, and to survey molecular mechanisms underlying post-traumatic epileptogenesis, which will guide the development of therapeutics for this currently untreatable condition.
