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MECHANISMS OF BRAIN DYSFUNCTION IN TUBEROUS SCLEROSIS

结节性硬化症脑功能障碍的机制

基本信息

批准号：
9263020
负责人：
MICHAEL WONG
金额：
$ 33.36万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-21 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9263020
关键词：
Address Affect Anti-Inflammatory Agents Anti-inflammatory Antiepileptogenic Astrocytes Autistic Disorder Benchmarking Brain Buffers Cells Cognitive deficits Complex Data Disease model Embryo Epilepsy Epileptogenesis FRAP1 gene Functional disorder Funding Gap Junctions General Population Genetic Glutamate Transporter Glutamates Grant Hereditary Disease High Prevalence Impaired cognition Impairment Inflammation Mediators Inflammatory Intellectual functioning disability Intervention Learning Disabilities Mediating Memory Mental Retardation Microglia Modeling Molecular Molecular Abnormality Morbidity - disease rate Mus National Institute of Neurological Disorders and Stroke Natural Immunity Neuroglia Neurologic Neurologic Deficit Neurologic Symptoms Neuronal Dysfunction Neurons Organ Pathogenesis Pathologic Pathway interactions Pharmacology Phenotype Play Population Research Potassium Process Property Public Health Publishing Research Role System TSC1 gene Testing Time Tuberous Sclerosis Tuberous sclerosis protein complex Work brain dysfunction cell type chemokine clinically significant cytokine disabling symptom improved inhibitor/antagonist innovation mortality mouse model nerve stem cell nervous system disorder neuron loss non-genetic novel novel therapeutic intervention novel therapeutics postnatal prevent public health relevance targeted treatment tumor

项目摘要

DESCRIPTION (provided by applicant): Tuberous sclerosis complex (TSC) is a genetic disorder, characterized by the formation of tumors in various organs, including the brain. Neurological manifestations, such as epilepsy, intellectual disability, and autism, are typically the most disabling symptoms of TSC. Advances in understanding the molecular pathogenesis of TSC have led to new therapies for tumors in TSC, particularly inhibitors of the mammalian target of rapamycin complex 1 (mTORC1) pathway. However, the pathophysiology of epilepsy and cognitive impairment in TSC is still poorly understood, and treatment of these disabling neurological symptoms remains limited. In previous funding periods of this grant, we utilized mouse models to investigate mechanisms of epileptogenesis in TSC (e.g. Tsc1GFAPCKO mice). We identified a number of cellular and molecular abnormalities in glia and neurons that contribute to epileptogenesis, such as astrocyte proliferation, impaired glial glutamate and potassium buffering, neuronal death, and dysregulation of mTORC1. Most remarkably, we provided evidence that mTORC1 inhibition has antiepileptogenic effects in preventing epilepsy and associated pathological abnormalities in mouse models of TSC, as well as in other models of acquired (non-genetic) epilepsy. In this grant renewal, we propose to extend our previous work by determining more specifically the contribution of non-neuronal cell types and innate immunity in contributing to the neurologic phenotype of TSC. Our general hypothesis is that non-neuronal cells, particularly astrocytes and microglia, play a critical role in the pathophysiology of epilepsy and other neurological manifestations of TSC, by activating inflammatory mechanisms in the brain. This proposal is innovative in focusing on the novel role of non-neuronal cells and innate immunity in the neurological phenotype of TSC. The proposal also has strong clinical significance and impact in testing new mechanistically-targeted therapies, which may benefit the neurological manifestations of not only TSC, but potentially also other neurological disorders.

描述(申请人提供)：结节性硬化症(TSC)是一种遗传性疾病，其特征是在包括大脑在内的各种器官中形成肿瘤。神经症状，如癫痫、智力残疾和自闭症，通常是TSC最致残的症状。随着对TSC分子发病机制认识的不断深入，针对TSC肿瘤的新的治疗方法，尤其是针对哺乳动物靶标雷帕霉素复合体1(MTORC1)通路的抑制剂，已经成为治疗TSC的新方法。然而，TSC癫痫和认知障碍的病理生理学机制仍然知之甚少，对这些致残性神经症状的治疗仍然有限。在这笔赠款的前几个资助期，我们利用小鼠模型来研究TSC(例如Tsc1GFAPCKO小鼠)癫痫发生的机制。我们在胶质细胞和神经元中发现了许多与癫痫发生有关的细胞和分子异常，如星形胶质细胞增殖，胶质细胞谷氨酸和钾缓冲功能受损，神经元死亡，以及mTORC1调节失调。最值得注意的是，我们提供了证据表明，在TSC的小鼠模型以及其他获得性(非遗传)癫痫模型中，mTORC1抑制在预防癫痫和相关的病理异常方面具有抗癫痫作用。在这次资助续期中，我们建议通过更具体地确定非神经细胞类型和先天免疫在TSC神经表型中的贡献来扩展我们之前的工作。我们的一般假设是，非神经细胞，特别是星形胶质细胞和小胶质细胞，通过激活大脑中的炎症机制，在癫痫和TSC的其他神经表现的病理生理学中发挥关键作用。这一建议在关注非神经细胞和先天免疫在TSC的神经学表型中的新作用方面具有创新性。该提案在测试新的机械靶向疗法方面也具有强大的临床意义和影响，这不仅可能有利于TSC的神经表现，而且可能有利于其他神经疾病。