Anti-epileptogenic role of mTOR activation among hippocampal interneurons

海马中间神经元 mTOR 激活的抗癫痫作用

• 批准号: 10362959
• 负责人: Steve C Danzer
• 金额: $ 49.28万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 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/10362959
• 关键词: Adaptor Signaling Protein; Affect; Animal Model; Animals; Antiepileptogenic; Benchmarking; Bilateral; Brain; Cells; Clinical; Conflict (Psychology); Dependovirus; Development; Disease; Disease model; Enterobacteria phage P1 Cre recombinase; Epilepsy; Epileptogenesis; FRAP1 gene; Feedback; Frequencies; Genetic; Genetic Models; Goals; Growth; Hippocampus (Brain); Impairment; Injections; Interneuron function; Interneurons; Kainic Acid; Metabolism; Modeling; Mus; Mutation; National Institute of Neurological Disorders and Stroke; Neurons; Parvalbumins; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Pilocarpine; Preventive treatment; Process; Raptors; Reporter; Rodent; Rodent Model; Role; SDZ RAD; Seizures; Series; Severities; Signal Transduction; Sirolimus; Somatostatin; Testing; Transgenic Organisms; Tuberous Sclerosis; United States; acquired epilepsy; antagonist; arm; brain cell; calmodulin-dependent protein kinase II; cell growth; design; excitatory neuron; experience; experimental study; genetic approach; genetic regulatory protein; improved; improved outcome; inhibitor; inhibitory neuron; innovation; preclinical study; prevent; preventable epilepsy; promoter; protective effect; recombinase; vector; vesicular GABA transporter

PROJECT SUMMARY Epilepsy can be a debilitating and sometimes fatal disease for which there are no preventatives, no cure, and for which existing medications fail in one third of patients. Development of preventative treatments for epilepsy is a key NINDS goal (Benchmark II. Prevent epilepsy and its progression; Galanopoulou et al., 2016; Binder et al., 2020). The mechanistic target of rapamycin (mTOR) pathway has emerged as a promising target for epilepsy prevention. mTOR acts as a relatively ubiquitous promotor of cell growth; enhancing neuronal connectivity, excitability and metabolism. Activation of the mTOR pathway occurs during epileptogenesis and appears to regulate pro-excitatory changes implicated in the process. Moreover, blocking mTOR signaling with the antagonist rapamycin mitigates epilepsy development in many epilepsy models. Blocking mTOR signaling, however, does not work in all models, and there is evidence that this pathway may also act to reduce brain excitability. To explain these conflicting effects, we hypothesize that increased mTOR activation among excitatory neurons is pro-epileptogenic, while activation among GABAergic interneurons is anti-epileptogenic. Systemic mTOR antagonists, therefore, block epileptogenic changes among excitatory cells, but also block compensatory protective changes among interneurons. To test this hypothesis, we will use intersectional genetic approaches to selectively delete the obligate mTOR regulatory proteins Raptor or Rictor from vesicular GABA transporter-, parvalbumin-, and somatostatin-expressing interneurons in mice. We will also examine the impact of enhancing mTOR signaling in interneurons by deleting the mTOR negative regulator Tsc2. Studies will be conducted using both acquired and genetic models of epilepsy. We predict that blocking mTOR signaling in interneurons will make epilepsy worse, while enhancing signaling will improve outcomes. Studies will advance understanding of the role of mTOR in epileptogenesis and will have direct implications for ongoing clinical use of mTOR antagonists.

项目总结 癫痫可以是一种衰弱的，有时甚至是致命的疾病，没有预防措施，不是吗？ 治愈，而现有的药物对三分之一的患者无效。预防性治疗的发展 治疗癫痫是NINDS的一个关键目标(基准二.预防癫痫及其进展；Galanopoulou等人， 2016；Binder等人，2020年)。雷帕霉素(MTOR)途径的机制靶点已经成为一个很有前途的靶点 癫痫预防的目标。MTOR作为一种相对普遍的细胞生长促进剂；增强 神经元连接、兴奋性和新陈代谢。MTOR通路的激活发生在 癫痫的发生，并似乎调节过程中涉及的前兴奋性变化。此外，屏蔽 在许多癫痫模型中，mTOR信号与拮抗剂雷帕霉素一起减轻癫痫的发展。 然而，阻断mTOR信号并不是在所有模型中都起作用，有证据表明这一途径可能 也可以降低大脑的兴奋性。为了解释这些相互冲突的影响，我们假设mTOR增加 兴奋性神经元的激活是致痫的，而GABA能中间神经元的激活是致痫的。 抗癫痫药。因此，全身性mTOR拮抗剂可阻断兴奋性 但也阻断了中间神经元之间的代偿性保护性变化。为了检验这一假设，我们将使用 选择性删除专有mTOR调控蛋白Raptor或Rictor的交叉遗传方法 来自囊泡状GABA转运体、小白蛋白和生长抑素表达的中间神经元。我们会 此外，还研究了通过删除mTOR负性来增强中间神经元中mTOR信号的影响 调节器TSC2。研究将使用癫痫的获得性模型和遗传模型进行。我们预测 阻断中间神经元中的mTOR信号将使癫痫恶化，而增强信号将改善癫痫 结果。研究将促进对mTOR在癫痫发生中的作用的理解，并将直接 MTOR拮抗剂的持续临床应用的意义。