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: 10161864
• 负责人: Detlev Boison
• 金额: $ 57.29万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161864
• 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 当前的癫痫疗法不足：至少30％的癫痫患者患有残留或医学 耐火性癫痫发作和/或合并症以及抗癫痫药的重要副作用。其中一些 这些患者通过生酮饮食（KD）成功治疗，理解不佳，并可能 未充分利用的代谢疗法于1921年成立。 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具有抗癫痫发作和疾病改良特性，最近的工作表明代谢 治疗可能会受益大大扩展的疾病范围，包括疼痛，自闭症，脑癌和 阿尔茨海默氏病。然而，KD的治疗用途主要限于小儿难治性 癫痫：几乎没有关于使用代谢疗法作为一线疗法的数据，因此它的真实临床 疗效和预防癫痫发生的能力尚不清楚。了解关键机制 KD的临床益处是紧迫的，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起源 具有疾病改良功能的癫痫功能的治疗剂。在这里，我们检验了我们的总体假设 在癫痫发生期间动员DNA甲基化的表观遗传学变化，并提供了A 通过基于饮食的代谢疗法预防癫痫的治疗靶标。在目标1中，我们将确定 （i）病因学上常见的临时啮齿动物模型（i）的表观遗传学癫痫机制 叶癫痫（TLE）和（ii）实验室独立 - 因此满足了癫痫研究的未满足需求 在我们的团队中建立高度严格的科学严谨性。在AIM 2中，我们将量化抗癫痫发生和 通过KD疗法动员的测试机制，包括增加腺苷作为下游的关键 抗癫痫发作机制。最后，在AIM 3中，我们将验证候选表观遗传变化是否为 基于KD的抗癫痫作用作用需要，从而为因果关系提供了机械证据 代谢疗法，表观遗传学改变和抗癫痫发生之间的关系。我们的方法 代表了对新陈代谢的首次系统和全面的机械分析 可以停止（甚至可以永久解决）癫痫发作的治疗。预期的结果是识别 和表观遗传机制的表征，代谢疗法会干扰 癫痫发生。特别是我们将确定是否预期 KD疗法和取决于鉴定的表观遗传机制。对 KD可能会揭示癫痫及其预防的全新疗法。

项目成果

The relationship between the neuromodulator adenosine and behavioral symptoms of autism.

• DOI: 10.1016/j.neulet.2011.06.007
• 发表时间: 2011-08-01
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Masino SA;Kawamura M Jr;Plotkin LM;Svedova J;DiMario FJ Jr;Eigsti IM
• 通讯作者: Eigsti IM

Homeostatic bioenergetic network regulation - a novel concept to avoid pharmacoresistance in epilepsy.

• DOI: 10.1517/17460441.2011.575777
• 发表时间: 2011-07
• 期刊: Expert opinion on drug discovery
• 影响因子: 6.3
• 作者: Boison D;Masino SA;Geiger JD
• 通讯作者: Geiger JD

Mu opioid receptor-mediated release of endolysosome iron increases levels of mitochondrial iron, reactive oxygen species, and cell death.

• DOI: 10.1515/nipt-2022-0013
• 发表时间: 2023-03-25
• 期刊: NeuroImmune pharmacology and therapeutics

Effects of a ketogenic diet on hippocampal plasticity in freely moving juvenile rats.

• DOI: 10.14814/phy2.12411
• 发表时间: 2015-05
• 期刊: Physiological reports
• 影响因子: 2.5
• 作者: Blaise JH;Ruskin DN;Koranda JL;Masino SA
• 通讯作者: Masino SA

The role of adenosine in alcohol-induced respiratory suppression.

• DOI: 10.1016/j.neuropharm.2022.109296
• 发表时间: 2023-01-01
• 期刊: NEUROPHARMACOLOGY
• 影响因子: 4.7
• 作者: Purnell, Benton S.;Thompson, Sydney;Bowman, Tenise;Bhasin, Jayant;George, Steven;Rust, Brian;Murugan, Madhuvika;Fedele, Denise;Boison, Detlev
• 通讯作者: Boison, Detlev