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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要目前的癫痫治疗方法还不够充分：至少 30% 的癫痫患者患有后遗症或药物治疗。难治性癫痫发作和/或合并症以及某些抗癫痫药物的显着副作用。这些患者通过生酮饮食 (KD) 获得成功治疗，这是一种人们知之甚少且可能存在的问题。 1921 年建立的代谢疗法尚未得到充分利用。生酮饮食在抑制难治性成人和儿童癫痫的癫痫发作已在多中心、国际和随机前瞻性临床研究和最近的转化工作强烈表明。 KD 具有抗癫痫和缓解疾病的特性，最近的研究表明代谢治疗可能有益于大大扩展的疾病范围，包括疼痛、自闭症、脑癌和然而，生酮饮食的治疗用途主要限于儿科难治性疾病。癫痫：实际上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。发挥 KD 的临床益处是紧迫的，并且具有最高的生物医学意义，因为它预计这些机制将导致有效的新的基于代谢的快速产生在这里，我们检验了我们的总体假设： DNA 甲基化的表观遗传变化在癫痫发生过程中被动员起来，并提供了在目标 1 中，我们将确定通过基于饮食的代谢疗法预防癫痫的治疗目标。表观遗传致癫痫机制是 (i) 病因学上不同的啮齿类动物模型所共有的叶性癫痫 (TLE) 和 (ii) 独立于实验室 - 从而满足癫痫研究和治疗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，我们将量化抗癫痫发生和治疗。 KD 疗法调动的测试机制，包括增加腺苷作为关键下游最后，在目标 3 中，我们将验证候选表观遗传变化是否有效。基于 KD 的抗癫痫作用所需，从而为因果关系提供机制证据代谢治疗、表观遗传改变和抗癫痫发生之间的关系。代表了对未被研究的代谢的第一个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方法的预期结果是识别。代谢疗法干扰这一过程的表观遗传机制的表征特别是，我们将确定预期的抗癫痫作用是否具有特异性。 KD 疗法依赖于已确定的表观遗传机制。 KD 可能会揭示一种全新的癫痫疗法及其预防方法。

项目成果

期刊论文数量（84）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
通讯作者：

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