mTOR regulation of aberrant neuronal integration and epileptogenesis in epilepsy

mTOR 对癫痫中异常神经元整合和癫痫发生的调节

基本信息

批准号：
9247850
负责人：
Steve C Danzer
金额：
$ 45.41万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-05 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247850
关键词：
Abnormal Cell Adaptor Signaling Protein Animal Model Animals Antiepileptogenic Axon Behavior Brain Cell physiology Cells Chemical Injury Complex Dendrites Development Disease Electroencephalography Epilepsy Epileptogenesis FRAP1 gene Frequencies Genes Genetic Genetic Models Hippocampus (Brain)Human Knock-out Mediating Modeling Molecular Target Monitor Mus Neuronal Plasticity Neurons Newborn Infant Output PTEN gene Pathologic Pathology Pathway interactions Patient risk Pharmaceutical Preparations Physiological Pilocarpine Population Property Prosencephalon Raptors Recurrence Regulation Reporter Role Seizures Signal Transduction Sirolimus Site Stem cells Syndrome Temporal Lobe Epilepsy Testing Tomatoes Transgenic Mice Translating Traumatic Brain Injury Whole-Cell Recordings Work analog base brain pathway cell motility controlled cortical impact effective therapy granule cell histological studies inhibitor/antagonist member nestin protein neuronal growth prevent public health relevance

项目摘要

DESCRIPTION (provided by applicant): There are currently no effective therapies for preventing epilepsy in at-risk patients. The mammalian target of rapamycin (mTOR), however, has emerged as a promising molecular target for the development of disease-modifying therapies. mTOR regulates a wide range of cellular processes through the signaling complexes mTORC1 and mTORC2. mTORC1 signaling is enhanced in chemical, injury-induced and genetic models of epilepsy, implying that the pathway could be involved in many different forms of the disease. Blocking mTOR signaling with the mTOR antagonist rapamycin appears to have anti-epileptogenic effects. Conversely, genetically enhancing mTOR signaling by deletion of upstream inhibitors produces spontaneous seizures in mice. Recent work from our lab further demonstrates that deletion of the mTOR inhibitor PTEN need only occur in a subset of newborn hippocampal dentate granule cells (DGCs) to produce the disease. PTEN knockout DGC developed the hallmark pathologies of the epileptic brain, including axon sprouting, ectopic cell migration and aberrant dendrite formation. The recurrent excitatory connections formed by pathological DGC are believed to destabilize the hippocampal circuit, promoting hyperexcitability and seizures. Despite clear evidence that dysregulation of the mTOR pathway can cause epilepsy in animals models and a small number of genetic epilepsy conditions in humans, however, the evidence that mTOR mediates epileptogenesis in acquired epilepsy syndromes is based entirely on correlational evidence and studies with the drug rapamycin and its analogs. Rapamycin is presumed to inhibit epileptogenesis by acting on mTORC1, and the site of action is presumed to be neurons; but these assumptions have not yet been experimentally proven. We hypothesize that in temporal lobe epilepsy, mTORC1 hyperactivation among newborn DGCs causes these neurons to integrate abnormally, and that these abnormal cells promote epileptogenesis. We also propose the alternate hypothesis, that mature hippocampal and cortical neurons drive epileptogenesis. To assess the role of mTOR activation in different neuronal populations, we will use conditional, inducible transgenic mouse strategies to delete mTOR from newborn granule cells or forebrain neurons. To test the role of different mTOR pathway members, we will delete the mTORC1 and mTORC2 adaptor proteins raptor and rictor, respectively. Finally, to determine whether the findings can be generalized, studies will be conducted in three different models of epilepsy. Together, these studies will reveal critical neuronal populations and identify druggable targets for the development of anti-epileptogenic therapies.

描述（由申请人提供）：目前尚无有效的疗法来预防高危患者的癫痫，然而，哺乳动物雷帕霉素靶点（mTOR）已成为开发疾病缓解疗法的有前景的分子靶点。 mTORC1 信号通过信号复合物 mTORC1 和 mTORC2 调节广泛的细胞过程，在癫痫的化学、损伤诱导和遗传模型中得到增强，这意味着该途径可能是通过使用 mTOR 拮抗剂雷帕霉素阻断 mTOR 信号传导似乎具有离线抗癫痫作用，通过删除上游抑制剂来遗传增强 mTOR 信号传导可在小鼠中产生自发性癫痫发作。 mTOR 抑制剂 PTEN 的缺失只需要在新生海马齿状颗粒细胞 (DGC) 的一个亚群中发生即可产生这种疾病。尽管有明确证据表明 mTOR 通路失调可导致动物模型癫痫，但病理性 DGC 形成的反复兴奋性连接被认为会破坏海马回路的稳定性，促进过度兴奋和癫痫发作。和少数人类遗传性癫痫病，然而，mTOR 介导获得性癫痫综合征中癫痫发生的证据完全基于雷帕霉素及其类似物的相关证据和研究推测雷帕霉素通过作用于 mTORC1 来抑制癫痫发生，并且推测作用部位是神经元；但这些假设尚未在颞叶中得到实验证明。癫痫，新生 DGC 中 mTORC1 过度激活导致这些神经元异常整合，并且这些异常细胞促进癫痫发生。为了评估 mTOR 激活在不同神经元群体中的作用，我们将使用条件性诱导转基因小鼠策略从新生颗粒细胞或前脑神经元中删除 mTOR。最后，为了确定这些研究结果是否可以推广，我们将在三种不同的癫痫模型中进行这些研究。将揭示关键的神经元群体并确定用于开发抗癫痫疗法的药物靶点。