MECHANISMS OF BRAIN DYSFUNCTION IN TUBEROUS SCLEROSIS

描述(由申请人提供)：结节性硬化症(TSC)是癫痫最常见的遗传原因之一。此外，TSC中的癫痫通常非常严重，对现有的治疗方法来说很难治愈。目前大多数癫痫的治疗方法都是简单的对症治疗，可能会抑制癫痫发作，但不一定能纠正导致癫痫的潜在大脑异常。因此，了解导致癫痫的大脑机制(“癫痫发生”)对于开发更有效的TSC和非TSC相关癫痫的“抗癫痫”治疗方法是必要的。我们之前已经描述了一种TSC的小鼠模型，它概括了人类TSC(Tsc1GFAPCKO小鼠)的许多特征，包括严重癫痫。在这笔赠款的第一个资助期，我们描述了导致这些小鼠癫痫发生的胶质细胞和神经元中的一些细胞和分子异常，如星形胶质细胞增殖、神经元死亡、神经递质和钾离子的神经胶质缓冲功能受损，以及特定细胞信号通路的异常调节。最值得注意的是，我们发现对其中一个信号通路的药物抑制，即雷帕霉素(MTOR)通路的哺乳动物靶点，完全阻止了Tsc1GFAPCKO小鼠癫痫的发展，这是在任何癫痫模型中首次展示了强大的抗癫痫作用。在这项授权续期申请中，我们建议扩展我们之前的工作，现在进一步表征参与癫痫发生的特定TSC调节的信号通路。我们的一般假设是，癫痫的发生主要是由于特定细胞信号通路的初始异常，纠正这些信号异常可能会阻止Tsc1GFAPCKO小鼠以及其他癫痫模型的癫痫发生。这笔赠款的发现将有助于确定癫痫发生的新机制，并确定新的抗癫痫治疗方法，不仅适用于TSC的癫痫，而且可能适用于所有癫痫。 公共卫生相关性：癫痫影响约1-2%的所有人，并与死亡率增加以及显著的神经疾病相关，如记忆障碍、学习障碍和智力低下。这项赠款的研究旨在确定结节性硬化症复合体以及其他癫痫模型的癫痫发生机制，结节性硬化症是癫痫最常见的遗传原因之一，并开发新的“抗癫痫”治疗方法，不仅抑制癫痫发作，而且实际上纠正导致癫痫的潜在大脑异常。因此，鉴于癫痫在普通人群中的高患病率，这项研究与公共卫生具有很强的相关性，并有可能对改善公共卫生产生重大的积极影响。

DESCRIPTION (provided by applicant): Tuberous Sclerosis Complex (TSC) is one of the most common genetic causes of epilepsy. In addition, epilepsy in TSC is typically very severe and intractable to available therapies. Most current treatments for epilepsy are simply symptomatic therapies that may suppress seizures but do not necessarily correct the underlying brain abnormalities causing the epilepsy. Thus, understanding the brain mechanisms causing epilepsy ("epileptogenesis") is necessary to develop more effective, "anti-epileptogenic" treatments for both TSC and non-TSC-related epilepsy. We have previously described a mouse model of TSC that recapitulates many features of human TSC (Tsc1GFAPCKO mice), including severe epilepsy. In the first funding period of this grant, we have described a number of cellular and molecular abnormalities in glia and neurons that contribute to epileptogenesis in these mice, such as astrocyte proliferation, neuronal death, impaired glial buffering of neurotransmitters and potassium ions, and abnormal regulation of specific cell signaling pathways. Most remarkably, we showed that pharmacological inhibition of one of these signaling pathways, the mammalian target of rapamycin (mTOR) pathway, completely prevented the development of epilepsy in Tsc1GFAPCKO mice, representing one of the first demonstrations of a robust anti-epileptogenic effect in any epilepsy model. In this grant renewal application, we propose to extend our previous work, now further characterizing specific TSC-regulated signaling pathways involved in epileptogenesis. Our general hypothesis is that epileptogenesis results primarily from initial abnormalities in specific cell signaling pathways and correction of these signaling abnormalities may prevent epileptogenesis in Tsc1GFAPCKO mice, as well as in other epilepsy models. Findings from this grant should help identify novel mechanisms of epileptogenesis and identify new anti- epileptogenic therapeutic approaches not only for epilepsy in TSC, but potentially for all epilepsy in general. PUBLIC HEALTH RELEVANCE: Epilepsy affects ~1-2% of all people and is associated with increased mortality, as well as significant neurological morbidity, such as memory difficulties, learning disabilities, and mental retardation. The research in this grant aims to determine mechanisms of epileptogenesis in Tuberous Sclerosis Complex, one of the most common genetic causes of epilepsy, as well as in other models of epilepsy, and to develop novel "anti- epileptogenic" therapeutic approaches that do not just suppress seizures but actually correct the underlying brain abnormalities causing epilepsy. Thus, given the high prevalence of epilepsy in the general population, this research has strong relevance to public health and has the potential to have a significant positive impact in improving public health.