Mitochodrial Dynamics in Metabolism-based Therapies for Epilepsy

癫痫代谢疗法中的线粒体动力学

• 批准号: 8110805
• 负责人: Adam L Hartman
• 金额: $ 17.61万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110805
• 关键词: Acute; Affect; Anticonvulsants; Astrocytes; Autophagocytosis; Biogenesis; Biomass; Caloric Restriction; Cells; Child; Childhood; Clinical Treatment; Data; Dependence; Development; Development Plans; Diet; Diet Modification; Disease; Electron Microscopy; Epilepsy; Fasting; Future; Glutamates; Goals; Hippocampus (Brain); Immunohistochemistry; Institution; Intractable Epilepsy; Lead; Leucine; Life; Lipids; Maintenance; Measures; Medicine; Mentors; Mentorship; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Molecular Target; Morphology; Mus; Neocortex; Neurons; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Population; Principal Investigator; Process; Proteins; Public Health Schools; Reporting; Research Personnel; Research Proposals; Resectable; Rodent; Role; Seizures; Signal Transduction; Sirolimus; Specificity; Synapses; System; Testing; Training; Work; base; carbohydrate metabolism; career development; cell growth; cell type; design; detection of nutrient; dietary restriction; experience; human FRAP1 protein; inhibitory neuron; innovation; ketogenic diet; mTOR Inhibitor; mTOR inhibition; mouse model; neuronal cell body; neurotransmitter release; novel; novel strategies; novel therapeutics; professor; randomized trial; research and development; role model; tool

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. PUBLIC HEALTH RELEVANCE: Over one-third of patients with epilepsy do not respond to the available drugs. One option for these patients is the ketogenic diet, which significantly decreases seizures in one half of patients who use it. However, essentially nothing is known about the anticonvulsant mechanisms involved. This proposal pursues a potential underlying mechanism of the ketogenic diet in epilepsy and is expected to identify a specific molecular target that will guide future development of new therapeutic strategies.

描述（由申请人提供）：该提案提供了一个指导的职业发展计划和研究提案，旨在促进主要研究者过渡到独立的临床研究人员。癫痫在生命的某个阶段影响约1.7%的美国人口，约33%的患者癫痫发作无法通过药物控制。这一组的选择是有限的，但一种古老的治疗方法，生酮饮食，在最近的一项随机试验中显示，在三个月内，诱导儿童癫痫发作减少75%（与等待开始饮食的儿童相比）。然而，饮食的抗惊厥作用的机制尚不清楚。生酮饮食引起代谢的重大变化。mTOR通路整合了多种代谢信号，其抑制导致许多变化，包括细胞组分（包括线粒体）的降解。线粒体降解还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，例如维持神经元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应途径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）确定营养物感应途径在基于代谢的抗惊厥治疗中的作用;（2）确定生酮饮食作用的细胞类型特异性;和（3）确定生酮饮食对线粒体动力学的作用，以及这些作用对mTOR的依赖性。这些研究有望确定癫痫治疗的新靶点，并揭示基于代谢的治疗机制。这些信息对于开发比饮食调整更有效、更方便实施的临床治疗方法将是有价值的。详细介绍了个性化的职业发展计划。这项建议将在约翰霍普金斯公共卫生和医学学院的大卫博迪安教授J.玛丽哈德威克博士的指导下进行，他是线粒体动力学和调节这些过程的因素的专家。该计划利用有经验的合作者的专门知识，并包括有关培训的具体计划。约翰霍普金斯是国际公认的儿科癫痫中心，是少数几个连续实施不同类型的基于代谢的癫痫治疗超过70年的机构之一。主要研究者的长期目标是为确定治疗儿童难治性癫痫的新靶点做出重大贡献。 公共卫生相关性：超过三分之一的癫痫患者对现有药物无反应。这些患者的一个选择是生酮饮食，使用它的一半患者的癫痫发作明显减少。然而，基本上对所涉及的抗惊厥机制一无所知。该提案寻求生酮饮食在癫痫中的潜在机制，并有望确定一个特定的分子靶点，以指导未来新治疗策略的开发。