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）：结节性硬化症复合物（TSC）是癫痫的最常见遗传原因之一。此外，TSC中的癫痫通常非常严重且对可用疗法棘手。目前对癫痫的大多数治疗方法只是可能抑制癫痫发作的症状疗法，但不一定纠正导致癫痫的潜在脑异常。因此，了解引起癫痫的大脑机制（“癫痫生成”）对于开发针对TSC和非TSC相关癫痫的更有效的“抗癫痫病”治疗是必要的。我们先前已经描述了TSC的小鼠模型，该模型概括了人类TSC（TSC1GFAPCKO小鼠）的许多特征，包括严重的癫痫。在这笔赠款的第一个资金期间，我们描述了在这些小鼠中导致癫痫发生的许多细胞和分子异常，例如星形胶质细胞增殖，神经元死亡，神经递质和钾离子和钾离子异常信号path的神经递质和钾质递质的神经胶质缓冲受损。最值得注意的是，我们表明，这些信号通路之一的药理抑制是雷帕霉素（MTOR）途径的哺乳动物靶标，完全阻止了TSC1GFAPCKO小鼠中癫痫的发展，代表了任何癫痫效应在任何癫痫症模型中的最早证明之一。在此赠款更新应用中，我们建议扩展我们以前的工作，现在进一步表征与癫痫发生有关的特定TSC调节的信号通路。我们的总体假设是，癫痫发生主要是由于特定细胞信号通路中的初始异常和对这些信号传导异常的校正可能导致的，可能会阻止TSC1GFAPCKO小鼠以及其他癫痫模型中的癫痫发生。该赠款的发现应有助于确定癫痫发生的新型机制，并确定新的抗癫痫病治疗方法不仅用于TSC中的癫痫病，而且可能对所有癫痫病的所有癫痫病。 公共卫生相关性：癫痫会影响所有人的约1-2％，并与死亡率增加以及明显的神经系统发病率有关，例如记忆困难，学习障碍和智力低下。该赠款中的研究旨在确定结节性硬化症复合物中癫痫生成的机制，这是癫痫的最常见遗传原因之一，以及其他癫痫模型，并开发出新颖的“抗癫痫病”治疗方法，它不仅抑制了癫痫发作，而且实际上抑制了脑部的脑部伯爵症状，而实际上是抑制了脑部的衰老。因此，鉴于普通人群中癫痫病的高度流行，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积极影响。