Epileptogenesis: Causes, Consequences and Treatment

癫痫发生：原因、后果和治疗

• 批准号: 7626470
• 负责人: DOUGLAS A COULTER
• 金额: $ 128.3万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7626470
• 关键词: Epileptogenesis; Causes; Consequences; Treatment

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（由申请人提供）：颞叶癫痫（TLE）是成年人中最常见的癫痫综合症，也是最棘手的癫痫综合症。这是一种有症状的疾病，即与先前的侮辱相关的情况。脑损伤后病理，癫痫发生改变的过程在很大程度上尚不清楚。该提案的目的是阐明癫痫发作对大脑引发的机制，这些机制结合起来使初始损伤难以治疗，并继续引发一系列级联的事件，最终在癫痫病中。一旦确定了癫痫发生过程中的关键事件，就要开始进行其他研究以干预这些病理过程的发展，并评估这是否会降低或阻止随后的癫痫发育的严重性。该计划结合了三位主要研究者的专业知识，并在神经生理学，生物化学和分子生物学方面的专业知识结合了专业知识。这种方法的结合允许研究人员之间的协同相互作用，并且构成了该计划的重要优势。使用电生理学，分子，生化和整个动物方法的结合，本提案将阐明1）抑制性突触中损伤引发的代谢过程的变化如何损害抑制性抑制疗效，并使海马对tle的海马产生损害； 2）如何通过继续诱导癫痫病的脑损伤来改变GABA受体的运输，以及这些运输的改变可能有助于癫痫持续性癫痫病的渐进性促进性，以及3）确定旨在阻止癫痫受害动物的动物发展的癫痫症状的干预措施是否可以阻止癫痫症状的效率促进ePilepsise epepsise contibles有效。了解在功能，分子和整个动物水平上癫痫发生变化的性质是促进新的治疗策略发展以更好地治疗或治愈这种进步和破坏性疾病的绝对先决条件。