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

• 批准号: 8887821
• 负责人: Steve C Danzer
• 金额: $ 38.58万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 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/8887821
• 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; Frequencies; Genes; Genetic; Genetic Models; Hippocampus (Brain); Human; Knock-out; Mediating; Modeling; Molecular Target; Monitor; Mus; Neuronal Plasticity; Neurons; Newborn Infant; Output; PTEN gene; Pathology; Pathway interactions; Patient risk; Pharmaceutical Preparations; Physiological; Pilocarpine; Population; Property; Prosencephalon; Raptors; Recurrence; Regulation; Reporter; Role; Seizures; Signal Transduction; Sirolimus; Site; 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; inhibitor/antagonist; mTOR protein; member; nestin protein; neuronal growth; prevent; progenitor; public health relevance

 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)：目前还没有有效的治疗方法来预防高危患者的癫痫。然而，哺乳动物的雷帕霉素靶点(MTOR)已经成为开发疾病修改疗法的一个有前途的分子靶点。MTOR通过信号复合体mTORC1和mTORC2调节广泛的细胞过程。在化学、损伤诱导和遗传癫痫模型中，mTORC1信号被增强，这意味着该通路可能参与许多不同形式的疾病。用mTOR拮抗剂雷帕霉素阻断mTOR信号似乎有抗癫痫作用。相反，通过删除上游抑制物的基因增强mTOR信号会在小鼠中产生自发性癫痫发作。我们实验室最近的工作进一步表明，mTOR抑制剂PTEN的缺失只需要在新生海马齿状颗粒细胞(DGC)的一部分中发生，就会产生这种疾病。PTEN基因敲除DGC发展了癫痫脑的标志性病理，包括轴突萌发、异位细胞迁移和异常树突形成。病理性DGC形成的反复兴奋性连接被认为破坏了海马环路的稳定，促进了过度兴奋和癫痫发作。尽管有明确的证据表明mTOR通路的失调可以在动物模型中引起癫痫和在人类中引起少量的遗传性癫痫状况，但mTOR在获得性癫痫综合征中介导癫痫发生的证据完全基于相关证据和对药物雷帕霉素及其类似物的研究。雷帕霉素被认为是通过作用于mTORC1来抑制癫痫的发生，作用部位被认为是神经元；但这些假设尚未得到实验证明。我们假设，在颞叶癫痫中，新生DGC中mTORC1的过度激活导致这些神经元异常整合，这些异常细胞促进癫痫的发生。我们还提出了另一种假设，即成熟的海马神经元和皮质神经元驱动癫痫的发生。为了评估mTOR激活在不同神经元群体中的作用，我们将使用有条件的、可诱导的转基因小鼠策略从新生颗粒细胞或前脑神经元中删除mTOR。为了测试不同mTOR途径成员的作用，我们将分别删除mTORC1和mTORC2适配蛋白Raptor和Rictor。最后，为了确定这些发现是否可以推广，将在三种不同的癫痫模型中进行研究。总之，这些研究将揭示关键的神经元群体，并确定抗癫痫疗法开发的可用药靶点。