MECHANISMS OF BRAIN DYSFUNCTION IN TUBEROUS SCLEROSIS

结节性硬化症脑功能障碍的机制

• 批准号: 8073164
• 负责人: MICHAEL WONG
• 金额: $ 32.59万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-21 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073164
• 关键词: Accounting; Acute; Affect; Antiepileptogenic; Astrocytes; Behavioral; Binding; Brain; Buffers; Cessation of life; Chronic; Data; Development; Epilepsy; Epileptogenesis; Functional disorder; Funding; Gene Silencing; General Population; Genes; Genetic; Grant; Guanosine Triphosphate Phosphohydrolases; High Prevalence; Homologous Gene; Human; Lead; Learning Disabilities; Mediating; Memory; Mental Retardation; Modeling; Molecular; Molecular Abnormality; Morbidity - disease rate; Mus; Mutation; Neuroglia; Neurologic; Neurons; Neurotransmitters; Pathway interactions; Patients; Pentylenetetrazole; Phenotype; Population Research; Potassium Glutamate; Protein Biosynthesis; Proteins; Public Health; Regulation; Research; Seizures; Signal Pathway; Signal Transduction; Staging; Status Epilepticus; TSC1 gene; TSC2 gene; Testing; Therapeutic; Tuberous Sclerosis; Tuberous sclerosis protein complex; Work; cell growth; human TSC1 protein; human TSC2 protein; improved; kainate; mTOR protein; mortality; mouse model; novel; nucleophosmin; potassium ion; prevent; public health relevance; ras Proteins

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.

描述（由申请人提供）：多发性硬化症（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，并且对可用的疗法而言是难治的。目前大多数癫痫的治疗方法都是简单的对症治疗，可以抑制癫痫发作，但不一定纠正导致癫痫的潜在大脑异常。因此，了解导致癫痫（“癫痫发生”）的脑机制对于开发更有效的“抗癫痫”治疗TSC和非TSC相关癫痫是必要的。我们先前描述了一种小鼠TSC模型，该模型重现了人类TSC的许多特征（Tsc 1GFAPCKO小鼠），包括严重癫痫。在该资助的第一个资助期内，我们描述了一些胶质细胞和神经元的细胞和分子异常，这些异常有助于这些小鼠的癫痫发生，如星形胶质细胞增殖，神经元死亡，神经递质和钾离子的胶质缓冲受损，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，药理学抑制这些信号通路之一，雷帕霉素（mTOR）通路的哺乳动物靶点，完全阻止了Tsc 1GFAPCKO小鼠癫痫的发展，代表了在任何癫痫模型中强大的抗癫痫作用的第一个证明。在这项资助更新申请中，我们建议扩展我们以前的工作，现在进一步表征参与癫痫发生的特定TSC调节信号通路。我们的一般假设是，癫痫的结果主要是从特定的细胞信号通路的初始异常和纠正这些信号异常可能会防止癫痫发生Tsc 1GFAPCKO小鼠，以及在其他癫痫模型。这项资助的发现应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中的癫痫，而且可能适用于一般的所有癫痫。 公共卫生相关性：癫痫影响约1-2%的人，并与死亡率增加以及显著的神经系统发病率相关，如记忆困难、学习障碍和智力迟钝。这项研究旨在确定癫痫最常见的遗传原因之一--硬化症综合征以及其他癫痫模型的癫痫发生机制，并开发新型的“抗癫痫”治疗方法，不仅抑制癫痫发作，而且实际上纠正了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。