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：
10534198
负责人：
JEANNIE CHIN
金额：
$ 55万
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/10534198
关键词：
Acute Adverse effects Animal Model Anticonvulsants Antiepileptic Agents Antisense Oligonucleotides Behavior assessment 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 Measures Mediating Modeling Molecular Molecular Biology Molecular Genetics Mus Mutation Neurons PTEN gene Pathway interactions Pentylenetetrazole Periodicity Pharmaceutical Preparations Pharmacology Phenotype Phosphorylation Pilocarpine Prosencephalon Proteomics Public Health Publishing Recurrence Regulator Genes Role Seizures Signal Pathway Signal Transduction Sirolimus Technology Temporal Lobe Epilepsy Testing Therapeutic behavioral study cell type defined contribution experimental study humanized mouse improved in utero inhibitor insight interdisciplinary approach mTORopathies mouse genetics mouse model nervous system disorder neurophysiology novel novel therapeutics pharmacologic 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，对公共卫生构成了重大威胁，并负责巨大经济和社会负担。虽然某些抗癫痫药已证明对癫痫的治疗有益，但它们主要可减轻癫痫发作，并经常引起严重的不良反应。因此，新型治疗策略的发展至关重要。在这里，我们专注于哺乳动物的目标雷帕霉素（mTOR），通过两个不同的复合物mtorc1和mtorc2起作用，其功能障碍与癫痫有关。主要基于使用药物雷帕霉素慢性治疗的研究，目前认为MTORC1的过度激活导致与网络的异常节奏相关癫痫。但是，慢性雷帕霉素治疗也抑制了MTORC2的活性。因此，它仍然不清楚 MTORC1或MTORC2的过度激活是否导致异常同步神经元发射癫痫。该新应用的目的是定义MTOR信号激活的机制导致癫痫病，特别强调MTORC2。在AIM 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AIM 2中，使用磷蛋白质组学，遗传学，药理学和子宫电穿孔实验，我们将检查MTORC2抑制减少癫痫发作的机制。最后，在AIM 3中，我们将使用一种新颖的MTORC2的选择性和高效抑制剂，并评估其更广泛的在不同模型的癫痫模型中抑制癫痫发作的治疗潜力。