Mechanism and role of mTORC2 in seizure reduction

摘要 癫痫是一种神经疾病，对公共健康构成重大威胁，并导致巨大的 经济和社会负担。虽然一些抗癫痫药物已被证明对治疗癫痫有益， 它们主要提供癫痫的症状缓解，并经常造成严重的不良反应。因此， 开发新的治疗策略至关重要。在这里，我们关注的是哺乳动物的目标 雷帕霉素(MTOR)，通过两个不同的复合体mTORC1和mTORC2发挥作用，其功能障碍 与癫痫有关。这在很大程度上是基于使用药物雷帕霉素进行慢性治疗的研究， 目前认为，mTORC1的过度激活导致与以下相关的异常网络节律 癫痫。然而，慢性雷帕霉素治疗也抑制mTORC2的活性。因此，目前仍不清楚 MTORC1或mTORC2的过度激活是否导致脑内神经元的异常同步放电 癫痫。这一新应用程序的目标是定义激活mTOR信令的机制 导致癫痫，特别强调mTORC2。在目标1中，我们将使用分子遗传学来定义 MTOR复合体在癫痫发作中的作用。在目标2中，使用磷蛋白质组学、遗传学、药理学和子宫内 在电穿孔实验中，我们将研究抑制mTORC2减少癫痫发作的机制。 最后，在目标3中，我们将使用一种新的选择性和高效的mTORC2抑制剂，并评估其更广泛的应用 在不同癫痫模型中抑制癫痫发作的治疗潜力。

ABSTRACT Epilepsy is a neurological disorder that poses a major threat to public health and is responsible for an enormous economic and social burden. While some antiepileptic drugs have proven beneficial for the treatment of seizures, they mainly provide symptomatic relief from seizures and often cause serious adverse effects. Thus, the development of novel treatment strategies is of crucial importance. Here we focus on the mammalian target of rapamycin (mTOR), which functions via two distinct complexes mTORC1 and mTORC2, and whose dysfunction has been associated with epilepsy. Based largely on studies utilizing chronic treatment with the drug rapamycin, it is currently believed that hyperactivation of mTORC1 leads to abnormal network rhythmicity associated with epilepsy. However, chronic rapamycin treatment also inhibits the activity of mTORC2. Thus, it remains unclear whether hyperactivation of mTORC1 or mTORC2 leads to the abnormal synchronized neuronal firing during epilepsy. The goal of this new application is to define the mechanism by which activation of mTOR signaling leads to epilepsy, with a special emphasis on mTORC2. In Aim 1, we will use molecular genetics to define the role of mTOR complexes in seizures. In Aim 2, using phosphoproteomics, genetic, pharmacology and in utero electroporation experiments, we will examine the mechanism by which inhibition of mTORC2 reduces seizures. Finally, in Aim 3, we will use a novel selective and efficient inhibitor of mTORC2 and assess its broader therapeutic potential for the suppression of seizures in different models of epilepsy.