Identifying neurons and circuits critical for epileptogenesis

识别对癫痫发生至关重要的神经元和回路

基本信息

批准号：
8459027
负责人：
ISTVAN MODY
金额：
$ 29.72万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8459027
关键词：
Ablation Address Adult Affect Afghanistan Animals Antiepileptic Agents Apoptosis Apoptotic Behavioral Beryllium Biological Birth Blast Cell Blood Vessels Brain Brain Diseases Brain Injuries Caring Cell Aging Cell Death Cells Chemicals Chronic Chronic Phase Communities Craniocerebral Trauma Date of birth Development Devices Economic Burden Electric Stimulation Elements Epilepsy Epileptogenesis Family Fingerprint Generations Head Human In Vitro Incidence Indium Inflammation Injury Iraq Knowledge Life Light Mammals Mediating Mitosis Modeling Molecular Morbidity - disease rate Mus Neurologic Neurons Parahippocampal Gyrus Perforant Pathway Physiologic pulse Pilocarpine Plastics Play Population Prevention Process Property Recurrence Resistance Role Seizures Shock Slice Societies Soldier Staging Status Epilepticus Stroke Synapses Temporal Lobe Epilepsy Testing Time Toxin Translations Traumatic Brain Injury Veterans World Health Organization base cell age clinical practice critical period dentate gyrus entorhinal cortex gene therapy granule cell in vivo injured innovation insight mortality neurogenesis novel optogenetics prevent relating to nervous system research study tool

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：根据世界卫生组织 (WHO) 的数据，全世界有超过 5000 万人患有癫痫病。这种脑部疾病不仅影响患者，还影响他们的家人，并间接影响整个社区。美国约有 250 万癫痫患者，每年新增 150-20 万例，构成每年约 140 亿美元的经济负担。颞叶癫痫（TLE）是最常见的耐药性癫痫，由于反复发作和不可预测的癫痫发作，与显着的发病率和死亡率相关。在平民中，生命早期发生的神经损伤（头部外伤、癫痫持续状态、中风、炎症等）与“潜伏期”后发生 TLE 之间存在良好的相关性。除了平民之外，从伊拉克和阿富汗返回的美国退伍军人中，创伤后癫痫的发病率也可能急剧增加，因为简易爆炸装置产生的冲击波会产生包括血管损伤在内的新型脑损伤。有证据表明，61% 的回国士兵在爆炸中受到脑损伤，随后发生的创伤后癫痫症在该人群中可能会达到前所未有的比例。从脑损伤到慢性癫痫的转变被称为癫痫发生。由于缺乏对癫痫发生机制的了解，因此没有合理的药理学方法来预防癫痫。传统的抗癫痫药物 (AED) 无法有效防止正常大脑在突发性损伤后转变为癫痫大脑。目前的提议将通过检查三种不同类型的大脑损伤在细胞和回路水平上的共同潜在机制来解决我们对癫痫发生过程的认识上的主要差距。它将识别特定的神经元和回路，并测试这些神经元元素对于各种损伤后进展为 TLE 是否是必要和充分的。已经有一些间接证据表明，成人大脑中产生的神经元参与了这一过程。我们的中心假设是，在突发性脑损伤后导致 TLE 的癫痫发生的关键因素是一组齿状回颗粒细胞，这些细胞在其发育的最具塑性阶段被损伤“捕获”。这构成了癫痫发生的新概念模型，并且可以使用创新的光遗传学和化学分子生物学方法在癫痫发生过程中的特定时间激活或失活特定神经元进行充分测试。此外，电生理学和药理学研究将确定这些细胞和电路的独特特性。然后，它们特定的“指纹”可用于开发新型药理学或基因治疗工具，以阻止这些关键神经元件在脑损伤后产生慢性癫痫。新发现将有助于将我们的基本发现转化为临床实践。