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The mTOR pathway in neuronal death and epileptogenesis

mTOR 通路在神经元死亡和癫痫发生中的作用

基本信息

批准号：
8133694
负责人：
Yunfei Huang
金额：
$ 30.29万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-26 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8133694
关键词：
3-methyladenine Animal Model Attenuated Autophagocytosis Cause of Death Cell Death Cell physiology Cessation of life Chronic Clinical Clinical Trials Complex Data Development Diet Digestion Dominant-Negative Mutation Dose Epilepsy Epileptogenesis Genetic Growth Factor Health Hypoxia Immunosuppressive Agents Injury Intervention Ischemia Knockout Mice Lead Leucine Mediating Mediator of activation protein Medical Modeling Molecular N-Methyl-D-Aspartate Receptors N-Methylaspartate Nerve Degeneration Neurites Neurons Nutrient Organ Transplantation Organelles Oxidative Stress Pathway interactions Patients Pharmaceutical Preparations Phosphotransferases Prevention Preventive Process Proteins RNA Interference Raptors Receptor Activation Recycling Regulation Role Seizures Signal Pathway Sirolimus Starvation Status Epilepticus Stress Stroke Synapses Synaptic plasticity Testing Therapeutic Intervention Tonic - clonic seizures Transgenic Mice Translating Traumatic Brain Injury Tuberous sclerosis protein complex bafilomycin A1 cell growth improved inhibition of autophagy insight knock-down mTOR protein nervous system disorder neuron loss neuroprotection overexpression prevent prophylactic protein aggregate research study response stem therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Excessive activation of NMDA receptors (NMDAR) causes neuronal death, a process central too many neurological disorders, including traumatic injury, stroke, and seizure. Pre-conditional actions such as low-dose NMDA treatment, sub-lethal ischemia, or mild seizure can effectively prevent neuronal death caused by subsequent harsh insults, suggesting that mild stress conditions can be beneficial and indicating a possible niche for therapeutic intervention. We have recently established that NMDAR activation regulates the mammalian target of rapamycin (mTOR) pathway. This pathway, previously understood to influence cell growth in response to growth factors, nutrients, and other stress conditions, including oxidative stresses and hypoxia, may also regulate cell death. Our preliminary studies found that neuronal death elicited by NMDA treatment is attenuated upon leucine starvation, a stress condition that is known to inhibit the mTOR pathway. Several components of the mTOR pathway appear to be associated with epilepsy. To further elucidate the molecular mechanism of the mTOR pathway in neuronal death and its involvement in epileptogenesis, we will determine whether the pro- survival factor Akt, which acts both up- and downstream of mTOR, mediates the neuroprotection conferred by inhibition of mTOR (Aim I). Nutrient depletion and mTOR inhibition are known to activate the process of autophagy. We will determine whether autophagy is involved in neuroprotection (Aim II). Finally, we will determine whether inhibition of the mTOR pathway prevents neuronal loss in animal models of epilepsy and attenuates the development of spontaneous seizure (Aim III). Accomplishing the experiments proposed in these three aims will provide insight into the molecular mechanisms of mTOR in neuronal death and in epileptogenesis. Rapamycin (Sirolimus) has been used as immunosuppressant for organ transplantation and was recently put on clinical trial in patients with tuberous sclerosis complex (TSC). Furthermore, the leucine-starvation approach is clinically manageable in current medical settings. As epilepsy is a devastating neurological disorder with few preventive approaches available, any positive results from the proposed study could be readily translated into new clinical strategies for epilepsy prevention, presumably without many of the barriers normally encountered by traditional development of therapeutic drugs. PUBLIC HEALTH RELEVANCE Results from our studies will improve our understanding of the role of the mTOR signaling pathway in epilepsy as well as other neurological disorders such as stroke and traumatic brain injury. It may also lead to new pharmacological and diet interventions for those neurological disorders.

描述（由申请人提供）：NMDA 受体 (NMDAR) 的过度激活会导致神经元死亡，这是许多神经系统疾病的核心过程，包括创伤性损伤、中风和癫痫发作。低剂量 NMDA 治疗、亚致死性缺血或轻度癫痫等先决条件行动可以有效预防后续严重损伤引起的神经元死亡，这表明轻度应激条件可能是有益的，并表明治疗干预可能存在利基。我们最近确定 NMDAR 激活调节哺乳动物雷帕霉素靶点 (mTOR) 通路。此前人们认为，这条途径会影响细胞生长，以响应生长因子、营养物质和其他应激条件（包括氧化应激和缺氧），也可能调节细胞死亡。我们的初步研究发现，亮氨酸饥饿（一种已知会抑制 mTOR 通路的应激条件）时，NMDA 治疗引起的神经元死亡会减弱。 mTOR 通路的几个组成部分似乎与癫痫有关。为了进一步阐明 mTOR 通路在神经元死亡及其参与癫痫发生中的分子机制，我们将确定在 mTOR 上游和下游发挥作用的促生存因子 Akt 是否介导通过抑制 mTOR 所赋予的神经保护作用（目标 I）。众所周知，营养耗尽和 mTOR 抑制会激活自噬过程。我们将确定自噬是否参与神经保护（目标 II）。最后，我们将确定抑制 mTOR 通路是否可以防止癫痫动物模型中的神经元损失并减弱自发性癫痫发作的发展（目标 III）。完成这三个目标中提出的实验将深入了解 mTOR 在神经元死亡和癫痫发生中的分子机制。雷帕霉素（西罗莫司）已被用作器官移植的免疫抑制剂，最近在结节性硬化症（TSC）患者中进行了临床试验。此外，在当前的医疗环境下，亮氨酸饥饿方法在临床上是可以控制的。由于癫痫是一种毁灭性的神经系统疾病，几乎没有可用的预防方法，因此拟议研究的任何积极结果都可以很容易地转化为预防癫痫的新临床策略，大概不会遇到传统治疗药物开发通常遇到的许多障碍。公共卫生相关性我们的研究结果将提高我们对 mTOR 信号通路在癫痫以及其他神经系统疾病（如中风和创伤性脑损伤）中的作用的理解。它还可能导致针对这些神经系统疾病的新药理学和饮食干预措施。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Noninflammatory Changes of Microglia Are Sufficient to Cause Epilepsy.

DOI：
10.1016/j.celrep.2018.02.004
发表时间：
2018-02-20
期刊：
Cell reports
影响因子：
8.8
作者：
Zhao X;Liao Y;Morgan S;Mathur R;Feustel P;Mazurkiewicz J;Qian J;Chang J;Mathern GW;Adamo MA;Ritaccio AL;Gruenthal M;Zhu X;Huang Y
通讯作者：
Huang Y

Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy.

DOI：
10.1016/j.nbd.2010.05.024
发表时间：
2010-10
期刊：
Neurobiology of disease
影响因子：
6.1
作者：
Huang X;Zhang H;Yang J;Wu J;McMahon J;Lin Y;Cao Z;Gruenthal M;Huang Y
通讯作者：
Huang Y

Seizure-dependent mTOR activation in 5-HT neurons promotes autism-like behaviors in mice.

5-HT神经元中的癫痫发作依赖性mTOR激活促进了小鼠的自闭症行为。

DOI：
10.1016/j.nbd.2014.10.004
发表时间：
2015-01
期刊：
NEUROBIOLOGY OF DISEASE
影响因子：
6.1
作者：
McMahon, John J.;Yu, Wilson;Yang, Jun;Feng, Haihua;Helm, Meghan;McMahon, Elizabeth;Zhu, Xinjun;Shin, Damian;Huang, Yunfei
通讯作者：
Huang, Yunfei

Rapamycin attenuates aggressive behavior in a rat model of pilocarpine-induced epilepsy.