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.

项目总结 目前的癫痫治疗方法是不够的：至少30%的癫痫患者患有残留物或药物- 难治性癫痫发作和/或共病，以及抗癫痫药物的严重副作用。其中一些 这些患者成功地用生酮饮食(KD)治疗，这是一种鲜为人知的潜在的 未充分利用的代谢疗法成立于1921年。川崎病持续的临床成功抑制 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表明 KD具有抗癫痫和改善疾病的特性，最近的研究表明，代谢 治疗可能使更多的疾病受益，包括疼痛、自闭症、脑癌和 阿尔茨海默氏症。然而，KD的治疗应用在很大程度上局限于儿童难治性疾病。 癫痫：几乎没有使用代谢疗法作为一线治疗的数据，因此它是真正的临床治疗 预防癫痫发生的有效性和能力尚不清楚。了解通过哪些关键机制 发挥KD的临床益处迫在眉睫，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基础的快速形成 具有疾病修正能力的癫痫治疗药物。在这里，我们测试了我们的总体假设 DNA甲基化的表观遗传变化在癫痫发生过程中被动员起来，并提供了一种 以饮食为基础的代谢疗法预防癫痫的治疗目标。在目标1中，我们将确定 表观遗传致痫机制：(1)在不同的颞叶啮齿动物模型中具有共性 额叶癫痫(TLE)和(Ii)独立于实验室--从而满足了癫痫研究和治疗中未得到满足的需求 在我们的团队中建立起高度的科学严谨性。在目标2中，我们将量化抗癫痫的发生和 KD疗法动员的测试机制，包括作为关键下游的腺苷增加 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 以KD为基础的抗癫痫作用所必需的，从而为病因提供机械证据 代谢治疗、表观遗传学改变和抗癫痫作用之间的关系。我们的方法 首次对未被充分研究的新陈代谢进行了系统和全面的机制分析 可以阻止-甚至永久解决-癫痫发作的治疗。预期的结果是认同 和表观遗传机制的特征，通过代谢治疗干预的过程 癫痫的发生。特别是，我们将确定预期的抗癫痫作用是否特定于 KD治疗和依赖于已确定的表观遗传机制。从机械上透彻地理解 KD可能会揭示一种全新的癫痫治疗方法及其预防。