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Evaluating astrocyte loss after traumatic brain injury in initiation of post-traumatic epilepsy

评估创伤性脑损伤后引发创伤后癫痫的星形胶质细胞损失

基本信息

批准号：
10593792
负责人：
Stefanie Robel
金额：
$ 36.41万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10593792
关键词：
Ablation Acceleration Action Potentials Animal Model Animals Antiepileptic Agents Area Astrocytes Behavior Biology Blood Blood - brain barrier anatomy Brain Brain Concussion Brain Injuries Buffers Calcium Cells Complication Data Deceleration Development Diffuse Disease Drug Targeting Economic Burden Electroencephalography Electrophysiology (science)Endothelial Cells Epilepsy Epileptogenesis Etiology Exclusion Extravasation Fractionation Freezing Functional disorder Hippocampus (Brain)Hour Human Image Impairment In Situ Incidence Injections Injury Interruption Intervention Ion-Exchange Chromatography Procedure Link Mannitol Measures Mechanics Modeling Molecular Monitor Mus Neuronal Dysfunction Neurons Patients Physiological Physiology Plant Roots Plasma Proteins Positioning Attribute Post-Traumatic Epilepsy Potassium Glutamate Preparation Process Property Proteins Risk Seizures Signal Transduction Site Techniques Testing Time Tissues Traumatic Brain Injury acquired epilepsy astrogliosis brain tissue hippocampal pyramidal neuron in vivo individual response mouse model nervous system disorder operation patch clamp prevent response social voltage sensitive dye

项目摘要

Project Summary After years of assuming that neurological diseases are caused by direct damage to neurons, we now know that impaired astrocyte physiology and function precedes and is essential for the progression of many of these diseases. This revelation hints toward the reason why anti-epileptic drugs that exclusively target neurons do not prevent the development of epilepsy after traumatic brain injury (TBI), the largest group of acquired epilepsies. For more than a decade, data have accumulated showing that astrocytes become reactive and lose their homeostatic functions indispensable for normal neuronal operation in epilepsy patients and animal models. Yet, a direct causal link between astrocyte dysfunction and post-traumatic epilepsy (PTE) has not been established beyond the fact TBI triggers astrogliosis. This may be in part due to the complexity of TBI, which induces many pathobiological mechanisms in parallel. Astrogliosis has mostly been studied in focal TBI, where layers of different types of reactive astrocytes surround a site of primary brain damage. Yet, this injury type presents in isolation in less than 10% of TBI patients and induces additional mechanisms that could trigger seizures, limiting our ability to determine if a causal relationship between astrocyte dysfunction and the development of PTE exists. Current PTE models are induced by focal TBI, but the vast majority of human TBIs include diffuse or concussive injury induced by rapid acceleration/deceleration of the brain tissue. Even patients who incur a single mild diffuse TBI are at increased risk for the development of PTE. Therefore, a new PTE mouse model that recapitulated diffuse TBI without focal injury was developed. This new PTE model induced spontaneous seizures at higher incidence than previous PTE models but with only a subset of cellular and tissue level changes, markedly reducing complexity of the underlying pathobiology. Data obtained in this model point to a surprisingly different response of astrocytes to diffuse TBI, suggesting that early loss of astrocytes may contribute to the development PTE. Yet, the upstream molecular mechanism inducing astrocyte loss and the downstream physiological consequences on neurons and neighboring astrocytes must be identified to ultimately find targets for interrupting the progression of TBI to PTE. This proposal aims to determine the primary cause for astrocyte loss using modified Folch extraction and fractionation techniques to narrow down the list of candidates. It further tests the hypothesis that astrocyte loss causes neurons and close-by astrocytes to become dysfunctional, initiating the formation of a seizure focus. This hypothesis will be tested using a combination of imaging, electrophysiology and EEG recordings in PTE mice or after specific ablation of cellular players. Given that the incidence of TBI has increased over the last decade, PTE as a lifelong complication of TBI is not only debilitating for those afflicted, but represents an ever-rising social and economic burden in the US. This proposal will examine astrocyte loss as a root cause initiating epileptogenesis after TBI, and will provide a basis for developing interventions that prevent the progression of TBI toward PTE.

项目摘要在多年来一直认为神经系统疾病是由神经元直接损伤引起的之后，我们现在知道了星形胶质细胞的生理和功能受损是其中许多疾病进展的先兆和关键疾病。这一发现暗示了为什么专门针对神经元的抗癫痫药物未预防发展为后天获得性脑损伤最大群体的创伤性脑损伤后癫痫癫痫。十多年来，积累的数据表明，星形胶质细胞变得有反应并丢失它们的稳态功能是癫痫患者和动物正常神经元操作所必需的模特们。然而，星形胶质细胞功能障碍和创伤后癫痫(PTE)之间的直接因果联系尚未得到证实建立在事实之外的脑外伤会触发星形胶质细胞增生症。这可能部分是由于TBI的复杂性，它同时引发了许多病理生物学机制。星形胶质细胞增生症主要是在局灶性脑损伤中研究的，不同类型的反应性星形胶质细胞层层环绕着初级脑损伤部位。然而，这种伤害类型在不到10%的脑损伤患者中孤立存在，并诱导可能触发的其他机制癫痫发作，限制了我们确定星形胶质细胞功能障碍与 PTE的发展是有的。目前的PTE模型是由局灶性脑损伤诱导的，但绝大多数人的脑损伤包括脑组织快速加速/减速引起的弥漫性或脑震荡损伤。连单发轻度弥漫性脑损伤的患者发生PTE的风险增加。因此，一个新的建立弥漫性脑损伤后无局灶性损伤的PTE小鼠模型。这款新的PTE型号与以前的PTE模型相比，诱发自发性癫痫的发生率更高，但只有一部分细胞和组织水平的变化，显著降低了潜在病理生物学的复杂性。在本表格中获得的数据模型指出星形胶质细胞对弥漫性脑损伤的反应令人惊讶地不同，这表明早期脑损伤的丧失星形胶质细胞可能参与PTE的发生。然而，诱导星形胶质细胞的上游分子机制必须确定损失及其下游对神经元和邻近星形胶质细胞的生理影响最终找到阻断脑外伤向PTE发展的靶点。这项提案旨在确定用改良的Folch提取和分级技术缩小星形胶质细胞损失的主要原因候选人名单。它进一步验证了星形胶质细胞丢失会导致神经元和邻近星形胶质细胞的假设变得功能失调，开始形成癫痫灶。这一假设将使用 PTE小鼠或细胞特异性消融后的影像、电生理和脑电记录的结合球员们。鉴于脑外伤的发病率在过去十年中有所增加，PTE作为一种终生并发症 TBI不仅使那些遭受痛苦的人虚弱，而且代表着世界上不断增加的社会和经济负担我们。这项建议将研究星形胶质细胞的丢失是脑外伤后引发癫痫的根本原因，并将为制定防止脑损伤向PTE发展的干预措施提供基础。