According to the World Health Organization (WHO), epilepsies affect over 50 million people worldwide. This brain disorder affects not only the sufferers but also their families and indirectly the entire community. The approximately 2.5 million epileptics in the US, with 150-200,000 cases added each year, constitute an annual economic burden of ~$14 billion. Temporal lobe epilepsy (TLE) is the most common form of pharmaco- resistant epilepsies and is associated with significant morbidity and mortality due to recurrent and unpredictable seizures. In the civilian population, there is a good correlation between the occurrence of a neurological insult earlier in life (head trauma, status epilepticus, stroke, inflammation, etc.) and the development of TLE after a "latent period". In addition to civilians, the incidence of posttraumatic epilepsy may increase drastically in the returning US veterans from Iraq and Afghanistan because the shock wave originating from Improvised Explosive Devices produces a novel type of brain injury including vascular damage. With evidence of brain injury in 61% of returning soldiers exposed to blasts, subsequent posttraumatic epilepsy is likely to reach unprecedented proportions in this population. The transition from brain insult to chronic epilepsy is termed epileptogenesis. In the absence of mechanistic insights into epileptogenesis, there is no rational pharmacological approach to its prevention. Conventional antiepileptic drugs (AEDs) are ineffective in preventing the conversion of a normal brain into an epileptic brain following a precipitating insult. The present proposal will address the major gap in our knowledge about the process of epileptogenesis by examining the common underlying mechanism at the cellular and circuit level of three different types of insult to the brain. It will identify specific neurons and circuits, and it will test whether these neuronal elements are necessary and sufficient for the progression to TLE following various insults. There is already some circumstantial evidence that neurons born in the adult brain are involved in this process. Our central hypothesis is that the key elements in epileptogenesis, leading to TLE following a precipitating brain insult, are a group of dentate gyrus granule cells that were "caught" by the insult at the most plastic stage of their development. This constitutes a new conceptual model of epileptogenesis and is fully testable using innovative novel optogenetic and chemical-molecular biological approaches to activate or inactivate specific neurons at specific times during the process of epileptogenesis. Moreover, electrophysiological and pharmacological studies will identify the distinguishing properties of these cells and circuits. Their specific "fingerprints" can then be used to develop novel pharmacological or gene therapy tools that will stop these critical neural elements from producing chronic epilepsy after a brain insult. The new discoveries will facilitate the translation of our basic findings into clinical practice.
It was previously thought that no new neurons could be generated in the adult brain. Over the past 10 years, this dogma has been demolished, and now we know that there is considerable and ongoing birth (neurogenesis) of new neurons in the brains of all mammals, including humans. Several insults to the brain including traumatic brain injury, stroke or status epilepticus can alter neurogenesis or can influence the way neurons at a certain stage of their development at the time of injury integrate into the existing circuitry of the brain. This proposal will investigate the role of the immature neurons that deviate from their normal integration into the functional circuitry following a large epilepsy-inducing insult to the brain. We will investigate how these cells become key players in generating abnormal synchronous neuronal activity that over time leads to full blown epilepsy (a process called epileptogenesis). Understanding the cellular and circuit mechanisms of epileptogenesis is expected to help prevent the development of epilepsy following status epilepticus, stroke, and traumatic brain injury, the latter being relevant to the numerous head-injured veterans. With about 1.4 million troops who served or are currently serving in Iraq/Afghanistan and a 50% chance of developing epilepsy after a traumatic brain insult, the prevention of epilepsy is an urgent necessity for the brave soldiers who suffered brain trauma, and for the society who will be paying for their care. NOTE: The purpose of the EUREKA initiative is to foster exceptionally innovative research that, if successful, will have an unusually high impact on the areas of science that are germane to the mission of one or more of the participating NIH Institutes. EUREKA is for new projects. EUREKA is not for the continuation of existing projects. EUREKA is not for support of pilot projects (i.e., projects of limited scope that are designed primarily to generate data that will enable the PI to seek other funding opportunities). Rather, it is anticipated that EUREKA projects will begin and be completed during the funding period. Please provide an overall impact/priority score to reflect your assessment of the likelihood the project will exert a sustained, powerful influence on the research field(s) involved, Significance and Innovation should be the major determinants of your overall impact score. The approach should be evaluated for general feasibility. An application should score poorly if it is clear to the reviewers that the proposed methodology has no probability at all of being successful, either because it is inherently illogical or because the same approach has already been attempted and shown not to be feasible. Remember that unavoidable risk, which is intrinsic to novel and innovative approaches, is expected for these applications and reviewers are instructed that the presence or absence of preliminary data should not be taken into account when determining the score. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.
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