The mTOR pathway in neuronal death and epileptogenesis

描述（由申请方提供）：NMDA受体（NMDAR）的过度激活导致神经元死亡，这是一种中枢神经系统疾病，包括创伤性损伤、中风和癫痫发作。预处理的行动，如低剂量的NMDA治疗，亚致死性缺血，或轻度癫痫发作可以有效地防止神经元死亡所造成的随后的苛刻的侮辱，这表明，温和的压力条件可以是有益的，并指示一个可能的利基治疗干预。我们最近已经确定，NMDAR激活调节哺乳动物雷帕霉素靶蛋白（mTOR）通路。这种途径，以前被理解为影响细胞生长，以响应生长因子，营养素和其他应激条件，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，由NMDA处理引起的神经元死亡在亮氨酸饥饿时减弱，亮氨酸饥饿是一种已知抑制mTOR通路的应激条件。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通路在神经元死亡中的分子机制及其参与癫痫发生，我们将确定促存活因子Akt（其作用于mTOR的上游和下游）是否介导由mTOR抑制赋予的神经保护（Aim I）。已知营养素消耗和mTOR抑制可激活自噬过程。我们将确定自噬是否参与神经保护（Aim II）。最后，我们将确定mTOR通路的抑制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（目的III）。完成这三个目标中提出的实验将提供深入了解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，亮氨酸饥饿方法在目前的医疗环境中是临床可管理的。由于癫痫是一种毁灭性的神经系统疾病，几乎没有预防方法，因此拟议研究的任何积极结果都可以很容易地转化为新的癫痫预防临床策略，大概没有传统治疗药物开发通常遇到的许多障碍。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）中作用的理解。它也可能导致新的药理学和饮食干预这些神经系统疾病。

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.