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：
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
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/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

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.

项目概要癫痫可能是一种使人衰弱甚至致命的疾病，目前没有预防措施，也没有治疗方法。治愈，并且现有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 II。预防癫痫及其进展；Galanopoulou 等人， 2016年；宾德等人，2020）。雷帕霉素（mTOR）通路的机制靶点已成为一种有前景的药物癫痫预防的目标。 mTOR 作为细胞生长相对普遍的促进剂；增强神经元连接性、兴奋性和新陈代谢。 mTOR 通路的激活发生在癫痫发生并似乎调节该过程中涉及的促兴奋性变化。此外，阻止 mTOR 信号传导与拮抗剂雷帕霉素可减轻许多癫痫模型中的癫痫发展。然而，阻断 mTOR 信号传导并非在所有模型中都起作用，并且有证据表明该途径可能还具有降低大脑兴奋性的作用。为了解释这些相互矛盾的影响，我们假设 mTOR 增加兴奋性神经元之间的激活是促癫痫的，而 GABA 能中间神经元之间的激活是致癫痫的。抗癫痫。因此，全身性 mTOR 拮抗剂可阻断兴奋性癫痫发作的变化。细胞，但也阻止中间神经元之间的代偿性保护变化。为了检验这个假设，我们将使用选择性删除专性 mTOR 调节蛋白 Raptor 或 Rictor 的交叉遗传方法来自小鼠中表达囊泡 GABA 转运蛋白、小白蛋白和生长抑素的中间神经元。我们将还检查通过删除 mTOR 阴性增强中间神经元中 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 信号传导会使癫痫恶化，而增强信号传导则会改善癫痫结果。研究将加深对 mTOR 在癫痫发生中的作用的理解，并将产生直接的影响。对 mTOR 拮抗剂持续临床使用的影响。