Ketogenic Diet and Adenosine: Epigenetics and Antiepileptogenesis

生酮饮食和腺苷：表观遗传学和抗癫痫发生

• 批准号: 9912862
• 负责人: Detlev Boison
• 金额: $ 54.69万
• 依托单位: TRINITY COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912862
• 关键词: Acute; Adenosine; Adult; Aftercare; Alzheimer' s Disease; Anticonvulsants; Antiepileptic Agents; Antiepileptogenic; Bioinformatics; Brain; Candidate Disease Gene; Childhood; Clinic; Clinical; Clinical Research; DNA Methylation; Data; Development; Diet; Diet therapy; Disease; Disease Progression; Drug usage; Epigenetic Process; Epilepsy; Epileptogenesis; Ethics; Etiology; Evaluation; Event; Female; Funding; Gene Expression; Genes; Goals; Hippocampus (Brain); Homeostasis; Ingestion; International; Intervention; Intractable Epilepsy; Kainic Acid; Laboratories; Link; Malignant neoplasm of brain; Measurement; Medical; Metabolic; Metabolism; Modeling; Mus; Neuromodulator; Newly Diagnosed; Onset of illness; Outcome; Pain; Pathway interactions; Patients; Prevention; Process; Property; Protocols documentation; Publishing; Randomized; Rattus; Refractory; Research; Research Design; Residual state; Rodent; Rodent Model; Seizures; Small Interfering RNA; Temporal Lobe Epilepsy; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Therapeutic Uses; Treatment Efficacy; Work; autism spectrum disorder; base; childhood epilepsy; clinical efficacy; clinically significant; cohort; comorbidity; design; disease diagnosis; epigenetic therapy; gene product; inhibitor/antagonist; ketogenic diet; male; novel; prevent; preventable epilepsy; prospective; sex; side effect; success; targeted treatment; therapeutic target; virtual

PROJECT SUMMARY Current epilepsy therapies are inadequate: at least 30% of epilepsy patients suffer residual or medically- refractory seizures and/or comorbidities as well as significant side-effects from antiepileptic drugs. Some of these patients are treated successfully with a ketogenic diet (KD), a poorly understood and potentially underutilized metabolic therapy established in 1921. The consistent clinical success of the KD in suppressing seizures in refractory adult and pediatric epilepsies has been verified in multi-center, international and randomized prospective clinical studies. Clinical observations and recent translational work strongly suggest that a KD has antiepileptogenic and disease-modifying properties, and recent work indicates that metabolic therapy may benefit a greatly expanded spectrum of diseases including pain, autism, brain cancer, and Alzheimer’s disease. Nevertheless, therapeutic use of the KD has been limited largely to pediatric refractory epilepsy: there are virtually no data on using a metabolic therapy as a first-line therapy, and thus its true clinical efficacy and ability to prevent epileptogenesis is unknown. Understanding key mechanisms by which the clinical benefits of a KD are exerted is urgent and of the highest biomedical significance because it is anticipated that these mechanisms will lead to the rapid genesis of effective new metabolism-based therapeutics with disease-modifying capabilities for epilepsy. Here we test our OVERALL HYPOTHESIS that epigenetic changes in DNA methylation are mobilized during epileptogenesis and provide a therapeutic target for epilepsy prevention through diet-based metabolic therapy. In Aim 1 we will identify epigenetic epileptogenic mechanisms that are (i) common to etiologically different rodent models of temporal lobe epilepsy (TLE) and (ii) laboratory independent – thus fulfilling an unmet need in epilepsy research and establishing a high degree of scientific rigor among our team. In Aim 2 we will quantify antiepileptogenesis and test mechanisms mobilized by KD therapy, including increased adenosine as a key downstream antiepileptogenic mechanism. Finally, in Aim 3 we will validate whether candidate epigenetic changes are required for KD-based antiepileptogenic effects and thereby provide mechanistic evidence for a causal relationship among metabolic therapy, epigenetic alterations, and antiepileptogenesis. Our approach represents the first systematic and comprehensive mechanistic analysis of an understudied metabolic treatment that can stop – and even permanently resolve – seizures. The expected outcome is the identification and characterization of epigenetic mechanisms through which metabolic therapy interferes with the process of epileptogenesis. In particular we will determine whether the expected antiepileptogenic effects are specific to KD-therapy and dependent on identified epigenetic mechanisms. A thorough mechanistic understanding of the KD may reveal an entirely new class of therapies for epilepsy and its prevention.

项目摘要 目前的癫痫治疗是不够的：至少30%的癫痫患者患有残余或医学- 难治性癫痫发作和/或合并症以及抗癫痫药物的显著副作用。一些 这些患者通过生酮饮食（KD）成功治疗，这是一种知之甚少且可能 1921年建立的未充分利用的代谢疗法KD在抑制KD中的一致临床成功 难治性成人和儿童癫痫发作已在多中心、国际和 随机前瞻性临床研究。临床观察和最近的翻译工作强烈建议 KD具有抗癫痫和改善疾病的特性，最近的研究表明代谢性 治疗可能会大大扩大疾病的范围，包括疼痛，自闭症，脑癌， 老年痴呆症然而，KD的治疗应用主要限于儿科难治性 癫痫：几乎没有关于使用代谢疗法作为一线疗法的数据，因此其真正的临床 预防癫痫发生的功效和能力尚不清楚。了解关键机制 发挥KD的临床益处是迫切的，并且具有最高的生物医学意义，因为它是 预计这些机制将导致有效的新代谢的快速发生， 具有改善癫痫疾病能力的治疗方法。在这里，我们测试我们的总体假设， DNA甲基化的表观遗传学变化在癫痫发生过程中被调动，并提供了一个 通过饮食代谢疗法预防癫痫的治疗目标。在目标1中，我们将确定 表观遗传性癫痫发生机制是（i）共同的病因不同的啮齿动物模型的时间 叶癫痫（TLE）和（ii）实验室独立-从而满足癫痫研究中未满足的需求， 在我们的团队中建立高度的科学严谨性。在目标2中，我们将量化抗癫痫作用， KD治疗动员的测试机制，包括增加腺苷作为关键下游 抗癫痫机制最后，在目标3中，我们将验证候选表观遗传变化是否是 这是基于KD的抗癫痫作用所需的，从而为因果关系提供了机制证据。 代谢治疗、表观遗传学改变和抗癫痫发生之间的关系。我们的方法 代表了第一个系统和全面的机制分析， 治疗可以停止-甚至永久解决-癫痫发作。预期的结果是， 和表征代谢治疗干扰代谢过程的表观遗传机制， 癫痫发生特别是，我们将确定预期的抗癫痫作用是否特异于 KD治疗和依赖于确定的表观遗传机制。彻底的机械理解 KD可能为癫痫及其预防提供一种全新的治疗方法。