Mitochodrial Dynamics in Metabolism-based Therapies for Epilepsy

描述(由申请人提供)：本提案提供了一个有指导的职业发展计划和研究提案，旨在促进首席研究员向独立的临床医生-研究员的转变。癫痫在一生中的某个时候影响着大约1.7%的美国人口，大约33%的患者有不能通过药物控制的癫痫发作。这一群体的选择有限，但最近的一项随机试验显示，生酮饮食是一种古老的治疗方法，可以在三个月内诱导儿童癫痫发作减少75%(与那些等待开始饮食的人相比)。然而，这种饮食的抗惊厥作用的机制还不清楚。生酮饮食会引起新陈代谢的重大变化。MTOR途径整合了多种代谢信号，它的抑制会导致许多变化，包括线粒体在内的细胞成分的降解。线粒体的降解也会影响控制线粒体定位和功能的关键神经元过程。线粒体在神经元中具有多种功能，如维持神经元的能量状态以维持电化学梯度和释放神经递质。线粒体的突触定位对于正常的突触形态和放电是至关重要的。我们的假设是，生酮饮食诱导的营养感知通路导致线粒体动力学和特定神经元亚群定位的变化。提出了三个目标：(1)确定营养感知通路在基于新陈代谢的抗惊厥治疗中的作用；(2)确定生酮饮食影响的细胞类型特异性；(3)确定生酮饮食对线粒体动力学的影响，以及这些影响对mTOR的依赖。这些研究有望为癫痫的治疗确定新的靶点，并揭示基于新陈代谢的治疗机制。这些信息将对开发比饮食修改更有效、更方便实施的临床治疗方法具有价值。详细介绍了个性化的职业发展计划。这项提议将在约翰霍普金斯大学公共卫生和医学院大卫·博迪安教授J·玛丽·哈德威克博士的指导下实施，他是线粒体动力学和调控这些过程的因素方面的专家。该计划利用了经验丰富的合作者的专业知识，并包括相关培训的具体计划。约翰霍普金斯大学是一家国际公认的儿童癫痫治疗中心，也是70多年来持续实施不同类型新陈代谢治疗癫痫的少数机构之一。主要研究人员的长期目标是在儿童难治性癫痫的治疗中为确定新的靶点做出重大贡献。

DESCRIPTION (provided by applicant): This proposal provides a mentored career development plan and research proposal designed to facilitate the principal investigator's transition to an independent clinician-researcher. Epilepsy affects ~1.7% of the US population at some point during life and ~33% of patients have seizures that are not controlled by medication. Options for this group are limited but one treatment from antiquity, the ketogenic diet, was shown in a recent randomized trial to induce a 75% decrease in seizures in children (vs those waiting to start the diet) over three months. However, the mechanisms of the diet's anticonvulsant actions are not understood. The ketogenic diet induces major changes in metabolism. The mTOR pathway integrates multiple metabolic signals and its inhibition leads to many changes, including degradation of cellular components including mitochondria. Mitochondrial degradation also affects key neuronal processes that govern mitochondrial localization and function. Mitochondria have multiple functions in neurons, such as maintaining neuronal energy status for the maintenance of electrochemical gradients and release of neurotransmitters. Synaptic localization of mitochondria is critical for normal synapse morphology and firing. Our hypothesis is that nutrient-sensing pathways induced by the ketogenic diet lead to changes in mitochondrial dynamics and localization in specific neuron subsets. Three goals are proposed: (1) determine the role of a nutrient-sensing pathway in metabolism- based anticonvulsant therapy; (2) determine the cell-type specificity of the effects of the ketogenic diet; and (3) determine the effects of the ketogenic diet on mitochondrial dynamics, and the dependence of these effects on mTOR. These studies are expected to identify new targets for the treatment of epilepsy and unravel the mechanisms of metabolism-based therapy. This information will be valuable for the development of clinical treatments that are more effective and more convenient to implement than dietary modification. An individualized career development plan is outlined in detail. This proposal will be carried out under the mentorship of Dr. J. Marie Hardwick, David Bodian Professor at Johns Hopkins Schools of Public Health and Medicine, an expert in mitochondrial dynamics and the factors that regulate these processes. The plan utilizes the expertise of experienced collaborators and includes specific plans for relevant training. Johns Hopkins is an internationally-recognized center for Pediatric Epilepsy and is one the few institutions where different types of metabolism-based therapy in epilepsy have been implemented continuously for over 70 years. The principal investigator's long-term goal is to make significant contributions towards identifying novel targets in the treatment of medically intractable epilepsy in children.