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:
- 金额:$ 49.28万
- 依托单位:
- 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:
- 关键词:Adaptor Signaling ProteinAffectAnimal ModelAnimalsAntiepileptogenicBenchmarkingBilateralBrainCellsClinicalConflict (Psychology)DependovirusDevelopmentDiseaseDisease modelEnterobacteria phage P1 Cre recombinaseEpilepsyEpileptogenesisFRAP1 geneFeedbackFrequenciesGeneticGenetic ModelsGoalsGrowthHippocampus (Brain)ImpairmentInjectionsInterneuron functionInterneuronsKainic AcidMetabolismModelingMusMutationNational Institute of Neurological Disorders and StrokeNeuronsParvalbuminsPathway interactionsPatientsPersonsPharmaceutical PreparationsPharmacologyPhenotypePilocarpinePreventive treatmentProcessRaptorsReporterRodentRodent ModelRoleSDZ RADSeizuresSeriesSeveritiesSignal TransductionSirolimusSomatostatinTestingTransgenic OrganismsTuberous SclerosisUnited Statesacquired epilepsyantagonistarmbrain cellcalmodulin-dependent protein kinase IIcell growthdesignexcitatory neuronexperienceexperimental studygenetic approachgenetic regulatory proteinimprovedimproved outcomeinhibitorinhibitory neuroninnovationpreclinical studypreventpreventable epilepsypromoterprotective effectrecombinasevectorvesicular 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 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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Steve C Danzer其他文献
Steve C Danzer的其他文献
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{{ truncateString('Steve C Danzer', 18)}}的其他基金
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:
10534188 - 财政年份:2021
- 资助金额:
$ 49.28万 - 项目类别:
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:
9247850 - 财政年份:2009
- 资助金额:
$ 49.28万 - 项目类别:
Identification and reversal of primary and secondary epileptogenic changes
原发性和继发性致癫痫变化的识别和逆转
- 批准号:
10599259 - 财政年份:2009
- 资助金额:
$ 49.28万 - 项目类别:
Selective disruption of hippocampal dentate granule cells in autism: impact of PT
自闭症患者海马齿状颗粒细胞的选择性破坏:PT 的影响
- 批准号:
8056038 - 财政年份:2009
- 资助金额:
$ 49.28万 - 项目类别:
Selective disruption of hippocampal dentate granule cells in autism: impact of PT
自闭症患者海马齿状颗粒细胞的选择性破坏:PT 的影响
- 批准号:
8254431 - 财政年份:2009
- 资助金额:
$ 49.28万 - 项目类别:
Short and long-term impact of neonatal seizures on hippocampal granule cell integ
新生儿癫痫发作对海马颗粒细胞整合的短期和长期影响
- 批准号:
7849034 - 财政年份:2009
- 资助金额:
$ 49.28万 - 项目类别:
Identification and reversal of primary and secondary epileptogenic changes
原发性和继发性致癫痫变化的识别和逆转
- 批准号:
8823832 - 财政年份:2009
- 资助金额:
$ 49.28万 - 项目类别:
Identification and reversal of primary and secondary epileptogenic changes
原发性和继发性致癫痫变化的识别和逆转
- 批准号:
9258491 - 财政年份:2009
- 资助金额:
$ 49.28万 - 项目类别:
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 - 财政年份:2009
- 资助金额:
$ 49.28万 - 项目类别:
Identification and reversal of primary and secondary epileptogenic changes
原发性和继发性致癫痫变化的识别和逆转
- 批准号:
9411798 - 财政年份:2009
- 资助金额:
$ 49.28万 - 项目类别:
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