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

基本信息

批准号：
10534188
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
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/10534188
关键词：
Adaptor Signaling Protein Affect Animal Model Animals Anticonvulsants Antiepileptogenic Benchmarking Bilateral Brain Cells Clinical Dependovirus Development Disease Disease model Enterobacteria phage P1 Cre recombinase Epilepsy Epileptogenesis FRAP1 gene Feedback Frequencies Genetic Genetic Models Goals Growth Hippocampus Impairment Injections Interneuron function Interneurons Kainic Acid LoxP-flanked allele Metabolism Modeling Mus Mutation National Institute of Neurological Disorders and Stroke Neurons Parvalbumins Pathway interactions Patients Persons Pharmaceutical Preparations Phenotype Pilocarpine Preventive treatment Process 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 neuroprotection pharmacologic preclinical study prevent preventable epilepsy promoter protective effect recombinase vector vesicular GABA transporter

项目摘要

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.

项目摘要癫痫可能是一种令人衰弱的，有时是致命的疾病，没有预防症，没有治愈，现有药物在三分之一的患者中失败。预防治疗的发展因为癫痫是一个关键的NINDS目标（基准II。预防癫痫及其进展； Galanopoulou等。 2016; Binder等人，2020年）。雷帕霉素（MTOR）途径的机械目标已成为有前途的预防癫痫的靶标。 MTOR充当细胞生长的相对普遍存在的启动子。增强神经元连通性，兴奋性和代谢。 MTOR途径的激活发生在癫痫发生，似乎调节了该过程中涉及的促兴趣变化。而且，阻止拮抗剂雷帕霉素的mTOR信号传导在许多癫痫模型中减轻癫痫发育。但是，阻止MTOR信号在所有模型中都没有起作用，并且有证据表明该途径可能还起作用，以降低大脑的兴奋性。为了解释这些矛盾的影响，我们假设增加了mtor 兴奋性神经元之间的激活是促发作性的，而GABA能中间神经元之间的激活为抗癫痫发作。因此，全身MTOR拮抗剂阻止了兴奋性的癫痫发生变化细胞，但也可以阻止中间神经元之间的补偿性保护性变化。为了检验这一假设，我们将使用有选择地删除强制性调节蛋白猛禽或rictor的相互遗传方法从小鼠的囊泡GABA转运蛋白转运蛋白，白蛋白蛋白和表达生长抑素的中间神经元。我们将还可以通过删除MTOR负阴性来检查增强中间神经元中MTOR信号传导的影响调节器TSC2。研究将使用癫痫的获得和遗传模型进行研究。我们预测阻断中间神经元中的MTOR信号传导会使癫痫病更糟，而增强信号会改善结果。研究将进一步了解MTOR在癫痫发生中的作用，并将直接对MTOR拮抗剂的临床使用的影响。