Epileptogenesis: Causes, Consequences and Treatment

癫痫发生：原因、后果和治疗

基本信息

批准号：
8073041
负责人：
DOUGLAS A COULTER
金额：
$ 129.4万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-15 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8073041
关键词：
Epileptogenesis Causes Consequences Treatment

项目摘要

DESCRIPTION (provided by applicant): Temporal lobe epilepsy (TLE) is the most common epileptic syndrome in adults, and also the most intractable. It is a symptomatic condition, i.e. one associated with a prior insult. The processes involved in generation of pathological, epileptogenic alterations following brain injury are largely unknown. The objectives of this proposal are to elucidate the mechanisms initiated by epileptogenic insults to the brain which combine to make the initial injury difficult to treat, and which go on to initiate a cascade of events culminating in epilepsy. Once pivotal events in the epileptogenic process are identified, additional studies are to be initiated to intervene in the development of these pathological processes, and assess whether this reduces the severity of or blocks the subsequent development of epilepsy. This program combines the expertise of three principal investigators, with expertise in neurophysiology, biochemistry, and molecular biology. This combination of approaches allows for synergistic interactions between investigators, and constitutes a significant strength of the program. Using a combination of electrophysiological, molecular, biochemical and whole animal approaches, the present proposal will elucidate 1) how injury-initiated changes in metabolic processes within inhibitory synapses compromise inhibitory efficacy and predispose the hippocampus to seizure generation in TLE; and 2) how GABA receptor trafficking may be altered by brain injuries which go on to induce epilepsy, and how these trafficking alterations may contribute to progressive intractabilty in status epilepticus, as well as 3) determine whether interventions designed to block metabolic and receptor trafficking alterations evident in animals following epileptogenic injuries may be viable strategies to block epilepsy development. Understanding the nature of epileptogenic changes at the functional, molecular, and whole animal level is an absolute prerequisite to facilitate the development of new therapeutic strategies to better treat and perhaps cure this progressive and devastating disorder.

描述（申请人提供）：颞叶癫痫（TLE）是成人最常见的癫痫综合征，也是最难治的。这是一种症状，即与先前的侮辱有关。脑损伤后产生病理性致癫痫改变的过程在很大程度上是未知的。该提案的目的是阐明由致癫痫性脑损伤引发的机制，这些机制结合起来使最初的损伤难以治疗，并继续引发一系列最终导致癫痫的事件。一旦确定了癫痫发生过程中的关键事件，就将启动更多研究来干预这些病理过程的发展，并评估这是否会减轻癫痫的严重程度或阻止癫痫的后续发展。该项目结合了三位主要研究人员的专业知识，以及神经生理学、生物化学和分子生物学方面的专业知识。这种方法的组合允许研究人员之间进行协同互动，并构成该计划的重要优势。结合电生理学、分子、生化和整体动物方法，本提案将阐明：1）抑制性突触内损伤引发的代谢过程变化如何损害抑制功效并使海马体易于在 TLE 中发生癫痫发作； 2) 脑损伤如何改变 GABA 受体的运输，进而诱发癫痫，以及这些运输的改变如何导致癫痫持续状态的逐渐难治性，以及 3) 确定是否需要采取干预措施来阻止代谢和受体运输的改变在致癫痫性损伤后的动物中显而易见，这可能是阻止癫痫发展的可行策略。了解功能、分子和整个动物水平上致癫痫变化的本质是促进开发新的治疗策略以更好地治疗甚至治愈这种进行性和破坏性疾病的绝对先决条件。