Mechanism and role of mTORC2 in seizure reduction

mTORC2 在减少癫痫发作中的机制和作用

基本信息

批准号：
10390854
负责人：
JEANNIE CHIN
金额：
$ 54.21万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-15 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10390854
关键词：
Acute Address Adverse effects Animal Model Anticonvulsants Antiepileptic Agents Antisense Oligonucleotides Behavioral Binding Biological Brain Cell physiology Chronic Complex Cre lox recombination system Data Development Economics Electroencephalography Electroporation Epilepsy Etiology FRAP1 gene Functional disorder Genetic Genetic Models Goals Human Individual Injections Kainic Acid Kinetics Lead Measures Mediating Modeling Molecular Molecular Biology Molecular Genetics Mus Mutation Neurons PTEN gene Pathway interactions Pentylenetetrazole Periodicity Pharmaceutical Preparations Pharmacology Phenotype Pilocarpine Prosencephalon Proteomics Public Health Publishing Raptors Recurrence Regulator Genes Role Seizures Signal Pathway Signal Transduction Sirolimus Technology Temporal Lobe Epilepsy Testing Therapeutic base behavioral study cell type defined contribution experimental study humanized mouse improved in utero insight interdisciplinary approach mTOR Inhibitor mTOR inhibition mTORopathies mouse genetics mouse model nervous system disorder neurophysiology novel novel therapeutics phosphoproteomics prevent social treatment strategy

项目摘要

ABSTRACT Epilepsy is a neurological disorder that poses a major threat to public health and is responsible for an enormous economic and social burden. While some antiepileptic drugs have proven beneficial for the treatment of seizures, they mainly provide symptomatic relief from seizures and often cause serious adverse effects. Thus, the development of novel treatment strategies is of crucial importance. Here we focus on the mammalian target of rapamycin (mTOR), which functions via two distinct complexes mTORC1 and mTORC2, and whose dysfunction has been associated with epilepsy. Based largely on studies utilizing chronic treatment with the drug rapamycin, it is currently believed that hyperactivation of mTORC1 leads to abnormal network rhythmicity associated with epilepsy. However, chronic rapamycin treatment also inhibits the activity of mTORC2. Thus, it remains unclear whether hyperactivation of mTORC1 or mTORC2 leads to the abnormal synchronized neuronal firing during epilepsy. The goal of this new application is to define the mechanism by which activation of mTOR signaling leads to epilepsy, with a special emphasis on mTORC2. In Aim 1, we will use molecular genetics to define the role of mTOR complexes in seizures. In Aim 2, using phosphoproteomics, genetic, pharmacology and in utero electroporation experiments, we will examine the mechanism by which inhibition of mTORC2 reduces seizures. Finally, in Aim 3, we will use a novel selective and efficient inhibitor of mTORC2 and assess its broader therapeutic potential for the suppression of seizures in different models of epilepsy.

抽象的癫痫是一种神经系统疾病，对公共健康构成重大威胁，并造成巨大的后果。经济和社会负担。虽然一些抗癫痫药物已被证明对治疗癫痫发作有效，它们主要缓解癫痫发作的症状，但往往会造成严重的不良反应。因此，开发新的治疗策略至关重要。这里我们重点关注哺乳动物的目标雷帕霉素 (mTOR)，通过两种不同的复合物 mTORC1 和 mTORC2 发挥作用，其功能障碍已与癫痫有关。主要基于利用雷帕霉素药物长期治疗的研究，目前认为，mTORC1 的过度激活会导致与以下疾病相关的异常网络节律性：癫痫。然而，长期雷帕霉素治疗也会抑制 mTORC2 的活性。因此，目前尚不清楚 mTORC1或mTORC2的过度激活是否会导致神经元放电异常同步癫痫。这个新应用的目标是定义 mTOR 信号传导激活的机制导致癫痫，特别是 mTORC2。在目标 1 中，我们将使用分子遗传学来定义 mTOR 复合物在癫痫发作中的作用。在目标 2 中，利用磷酸蛋白质组学、遗传学、药理学和子宫内通过电穿孔实验，我们将研究抑制 mTORC2 减少癫痫发作的机制。最后，在目标 3 中，我们将使用一种新型选择性且高效的 mTORC2 抑制剂，并评估其更广泛的用途在不同癫痫模型中抑制癫痫发作的治疗潜力。