Mechanisms of Brain Dysfunction in Tuberous Sclerosis

结节性硬化症脑功能障碍的机制

• 批准号: 7080206
• 负责人: MICHAEL WONG
• 金额: $ 22.87万
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7080206
• 关键词: astrocytes; brain; death; epilepsy; extracellular; glia; glutamate transporter; glutamates; potassium; potassium channel; role; tuberous sclerosis

DESCRIPTION (provided by applicant): Neurological complications, such as epilepsy, mental retardation, and autism, represent common sources of significant morbidity and mortality in children with tuberous sclerosis complex (TSC). Epilepsy, in particular, can be especially devastating and is often refractory to available treatments. Understanding the molecular, biochemical, and physiological mechanisms underlying epileptogenesis in TSC is critical to the development of more effective therapies for seizures in patients with TSC. Seizures and other neurological symptoms of TSC reflect the presence of characteristic developmental brain abnormalities, such as cortical tubers. Cortical tubers contain abnormally differentiated neuroglial cells and excessive gliosis, suggesting that glial cells may be important in the pathophysiology of epilepsy and brain dysfunction in TSC. To understand the contribution of glial cells to TSC brain dysfunction, we developed a novel mouse model of TSC (Tsc1[GFAP]CKO mice), in which Tsd inactivation in glia results in abnormalities in glial growth, proliferation, and differentation, neuronal disorganization, and severe epilepsy. The primary goal of this proposal is to elucidate the molecular, biochemical, and electrophysiological mechanisms by which glial defects in Tsd lead to seizures in Tsc1[GFAP]CKO mice. We hypothesize that glial Tsd inactivation results in impaired uptake of glutamate and potassium by astrocytes, which may promote epileptogenesis by causing abnormal extracellular glutamate and potassium homeostasis, excitotoxic neuronal death, and hyperexcitable neuronal circuits. In this project, we propose to determine the effects of glial Tsd inactivation on 1) the expression and function of specific astrocyte glutamate transporters and potassium channels, 2) extracellular glutamate and potassium levels, 3) induction of excitotoxic neuronal death, and 4) neuronal excitability on both the single cell and circuit levels in Tsc1[GFAP]CKO mice. Furthermore, the involvement of specific cellular signaling pathways, previously implicated in TSC, in mediating these effects will be investigated. In these studies, we will employ a unique combination of molecular genetic, biochemical, and electrophysiological approaches in the context of a successful, synergistic collaboration between two independent research laboratories to address these critical issues. In addition to defining the cellular and molecular mechanisms causing seizures specifically in TSC, these studies should provide broader insights into the general role of glial cells in epileptogenesis and identify novel therapies for seizures directed at astrocytes that may benefit all patients with epilepsy. Since epilepsy affects approximately 1% of all people, this research has the potential to have significant impact on public health.

描述（由申请人提供）：神经系统并发症，如癫痫、精神发育迟滞和自闭症，是结节性硬化症（TSC）儿童显著发病率和死亡率的常见来源。特别是癫痫，可能是特别具有破坏性的，并且通常对可用的治疗是难治的。了解TSC中癫痫发生的分子、生化和生理机制对于开发更有效的治疗TSC患者癫痫发作的疗法至关重要。TSC的癫痫发作和其他神经系统症状反映了特征性脑发育异常的存在，如皮质结节。皮质结节含有异常分化的神经胶质细胞和过度的胶质增生，这表明胶质细胞可能在TSC癫痫和脑功能障碍的病理生理学中起重要作用。为了了解胶质细胞对TSC脑功能障碍的贡献，我们开发了一种新的TSC小鼠模型（Tsc1[GFAP]CKO小鼠），其中胶质细胞中的Tsd失活导致胶质细胞生长、增殖和分化异常，神经元解体和严重癫痫。该建议的主要目标是阐明Tsd中胶质缺陷导致Tsc1[GFAP]CKO小鼠癫痫发作的分子，生化和电生理机制。我们假设胶质细胞Tsd失活导致星形胶质细胞对谷氨酸和钾的摄取受损，这可能通过引起异常的细胞外谷氨酸和钾稳态、兴奋性毒性神经元死亡和过度兴奋的神经元回路来促进癫痫发生。在这个项目中，我们建议确定胶质细胞Tsd失活对1）特定星形胶质细胞谷氨酸转运蛋白和钾通道的表达和功能，2）细胞外谷氨酸和钾水平，3）诱导兴奋性神经元死亡，和4）神经元兴奋性Tsc 1 [GFAP]CKO小鼠单细胞和回路水平的影响。此外，参与特定的细胞信号传导途径，以前涉及TSC，在介导这些影响将进行调查。在这些研究中，我们将采用分子遗传学，生物化学和电生理学方法的独特组合，在两个独立的研究实验室之间成功的协同合作的背景下，以解决这些关键问题。除了明确导致TSC癫痫发作的细胞和分子机制外，这些研究还应提供更广泛的见解，了解胶质细胞在癫痫发生中的一般作用，并确定针对星形胶质细胞的癫痫发作新疗法，这可能使所有癫痫患者受益。由于癫痫影响了大约1%的人，这项研究有可能对公共卫生产生重大影响。