Epilepsy is the third most common chronic neurological disorder, affecting 2.5 million persons in the USA. Temporal lobe epilepsy (TLE), with seizures involving the hippocampal circuit, is one of the most severe epilepsies in adults, and is refractory to medical treatment in >30% of individuals. TLE is commonly preceded by febrile status epilepticus (FSE). Whereas the relationship of FSE to human TLE is not fully understood, experimental FSE provokes TLE in animal models, suggesting that FSE might contribute to epileptogenesis in both normal and predisposed brain. Importantly, the contribution of FSE to TLE (as a 1st or 2nd hit) may be predictable and preventable. TLE commonly affects the young, exacting a tremendous toll on human potential. However, there are major challenges in preventing or aborting TLE: (1) We do not know the mechanisms for the contribution of FSE to TLE;(2) We do not have predictive markers to identify the 30-40% of those experiencing FSE who will proceed to develop TLE;(3) We do not have mechanism-based drugs to abort the epileptogenic process that bridges FSE and TLE. The three specific aims of this competing renewal proposal address these major challenges. We capitalize on results obtained during the current award period, on our published and novel findings regarding the molecular, cellular and network changes that follow FSE and contribute to epileptogenesis, and on exciting data supporting clinically-translatable predictive markers. We employ innovative methods in in vitro and in vivo systems, and integrate hypothesis-driven and large scale gene expression analyses. We devise innovative decoy and mimic approaches for both probing mechanistic questions and for potential translation. Our work to date has revolutionized the scientific approach to the study of febrile seizures and their consequences, has been published in high-impact journals and has been cited >4000 times. In this renewal application, we embark on highly novel, bench-derived yet translatable solutions to a major human health problem.

Public Health Relevance

Epilepsy is the third most common chronic neurological disorder, affecting 2.5 million persons in the USA. Temporal lobe epilepsy (TLE) is one of the most severe and difficult to treat epilepsies. This epilepsy is commonly preceded by febrile status epilepticus (FSE), and while the relationship of FSE to human TLE is not fully understood, in animal models, experimental FSE provokes TLE, suggesting that FSE might contribute to TLE in people. Importantly, the contribution of FSE to TLE (as a 1st or 2nd hit) may be predictable and preventable. TLE commonly affects the young, exacting a tremendous toll on human potential. Here we build on important information to answer three crucial questions (1) how does experimental FSE provoke TLE? (2) Can we predict early the 30-40% of individuals with FSE who will eventually develop TLE? (3) Can we use experimental drugs arising from our studies to abort epilepsy in individuals predicted to develop the disorder? Obviously, the ability to prevent epilepsy in children at high risk will make a huge difference.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS035439-16
Application #
8810580
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Fureman, Brandy E
Project Start
1997-04-01
Project End
2019-07-31
Budget Start
2014-09-01
Budget End
2015-07-31
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Irvine
State
CA
Country
United States
Zip Code
92697
Brennan, Gary P; Dey, Deblina; Chen, Yuncai et al. (2016) Dual and Opposing Roles of MicroRNA-124 in Epilepsy Are Mediated through Inflammatory and NRSF-Dependent Gene Networks. Cell Rep 14:2402-12
Patterson, Katelin P; Brennan, Gary P; Curran, Megan et al. (2015) Rapid, Coordinate Inflammatory Responses after Experimental Febrile Status Epilepticus: Implications for Epileptogenesis. eNeuro 2:
McClelland, Shawn; Brennan, Gary P; Dubé, Celine et al. (2014) The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes. Elife 3:e01267
Choy, ManKin; Dubé, Celine M; Patterson, Katelin et al. (2014) A novel, noninvasive, predictive epilepsy biomarker with clinical potential. J Neurosci 34:8672-84
Patterson, Katelin P; Baram, Tallie Z; Shinnar, Shlomo (2014) Origins of temporal lobe epilepsy: febrile seizures and febrile status epilepticus. Neurotherapeutics 11:242-50
Nakamura, Yuki; Shi, Xiuyu; Numata, Tomohiro et al. (2013) Novel HCN2 mutation contributes to febrile seizures by shifting the channel's kinetics in a temperature-dependent manner. PLoS One 8:e80376
Surges, Rainer; Kukley, Maria; Brewster, Amy et al. (2012) Hyperpolarization-activated cation current Ih of dentate gyrus granule cells is upregulated in human and rat temporal lobe epilepsy. Biochem Biophys Res Commun 420:156-60
Noam, Yoav; Phan, Lise; McClelland, Shawn et al. (2012) Distinct regional and subcellular localization of the actin-binding protein filamin A in the mature rat brain. J Comp Neurol 520:3013-34
Dedeurwaerdere, Stefanie; Friedman, Alon; Fabene, Paolo F et al. (2012) Finding a better drug for epilepsy: antiinflammatory targets. Epilepsia 53:1113-8
Marcelin, Béatrice; Lugo, Joaquin N; Brewster, Amy L et al. (2012) Differential dorso-ventral distributions of Kv4.2 and HCN proteins confer distinct integrative properties to hippocampal CA1 pyramidal cell distal dendrites. J Biol Chem 287:17656-61

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