Research Project: Epigenetic mechanisms of post-traumatic epilepsy
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Traumatic brain injury (TBI) is a major cause of mortality and morbidity in military SERVICE members and Veterans, which carries a large cost burden to society. TBI is a highly complex brain condition that inflicts long-lasting pain and suffering to affected persons and their family. As per the U.S. Centers for Disease Control and Prevention, an estimated 1.7 million individuals suffer a TBI annually in the United States. Post-traumatic epilepsy (PTE) with spontaneous seizures often occurs within a few months or years after TBI in up to 50% of cases, especially in penetrating brain injury among the Veterans. PTE is a devastating brain disease characterized by repeated seizures that are often medically uncontrollable. Despite such widespread devastation, the pathophysiology of PTE is poorly understood, and there is currently no drug therapy for preventing PTE in TBI-affected Soldiers and Veterans. A greater insight is required to advance the field of PTE; there is especially an urgent need to identify at least one critical underlying mechanism of PTE. A variety of mechanisms such as excitotoxicity, inflammation, and neuronal apoptosis are proposed, but epigenetic mechanisms are not studied in PTE. Epigenetics refers to specific changes in gene expression mediated by chromatin-based mechanisms. Epigenetic mechanisms, including DNA methylation, histone alterations, and RNA-based transcriptional control, can potentially alter a broader neuronal gene profile and thus regulate TBI pathology. Therefore, epigenetics is a revolutionary and powerful research tool for finding new frontiers on PTE in people at risk.
In this project, we seek to identify an epigenetic mechanism by which the brain controls hyperexcitability and seizures following TBI, with the ultimate goal of identifying the common mechanistic link between brain injury and the subsequent development of PTE. A more rational, effective strategy for preventing epilepsy is to target the primary signaling pathways that initially trigger the numerous downstream cellular and molecular mechanisms mediating epileptogenesis, the process whereby the brain becomes progressively epileptic because of injury factors. One signaling pathway, the histone deacetylation (HDAC) pathway, represents a logical candidate for such a mechanism, because diverse HDACs regulate multiple physiological functions in the brain, such as synaptic plasticity and ion channel expression, which may promote epileptogenesis under pathological conditions. Importantly, sodium butyrate, a drug that is tested for gastrointestinal and oncological conditions, can be used to inhibit the HDAC pathway and thus may represent a simple therapy for preventing PTE in at-risk people.
The main goal of this project is to investigate the epigenetic-based HDAC signaling pathway as a critical pathophysiological mechanism of PTE. We propose that long-lasting alterations in the epigenetic HDAC pathway, triggered due to TBI, will facilitate critical neuronal mechanisms leading to epileptogenesis. We will test this hypothesis by addressing two specific aims using a validated model of TBI in adult and middle-aged mice: Aim 1: To determine the alterations in the HDAC pathway and the functional consequences of HDAC inhibition on the development of PTE in a mouse CCI model. Aim 2: To determine whether targeted HDAC inhibition attenuates neurodegeneration and neurological dysfunction in a mouse CCI model of PTE. Recently, we identified the epigenetic HDAC pathway in mechanisms of epileptogenesis, and the HDAC inhibitor sodium butyrate has been proposed to have anti-epileptogenic effects in preventing or inhibiting acquisition of epilepsy.
In this "Idea Development" project, we propose a proof-of-concept study of whether similar HDAC mechanisms are involved in PTE and whether targeted HDAC inhibition prevents or modifies the development and retention of post-traumatic epileptogenesis with intractable seizures. We propose to use a controlled cortical impact (CCI) model, in which a piston-driven by electromagnetism impacts the head at a controlled angle, velocity, and depth. CCI, which is often delivered by a craniotomy, simulates aspects of concussions, brain contusion, and hemorrhage seen in human TBI. Post-traumatic seizures are monitored using continuous video-EEG (electroencephalogram) recording for 16 weeks following TBI. HDAC inhibitor treatment will be given starting 1 hour post-TBI for 4 weeks. The primary measures of protection include extent of post-traumatic seizures, neurodegeneration, neuroinflammation, mossy fiber sprouting, and cognitive dysfunction. Other key observations include checking seizure threshold, behavior dysfunction, and neurological/motor deficits. Our pilot studies prove the viability of accomplishing these goals. We have assembled a highly qualified team, and we possess all the facilities to implement this research within the project period.
This 3-year study will provide critical information on the mechanistic role of the HDAC pathway and the viability of an epigenetic HDAC inhibition strategy for the prophylaxis of TBI-induced epilepsy and neurodeficits in patients with TBI, notably military personnel and Veterans at high risk of epilepsy due to brain trauma.
Finally, this application is consistent with the goals of the Fiscal Year 2015 Epilepsy Research Program Idea Development Award mechanism, which is seeking applications in the focus areas of Markers and Mechanisms of PTE to support investigator-initiated research that may be high-risk and/or high-gain.
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