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（由适用提供）：结节性硬化症复合物（TSC）是一种遗传疾病，其特征是包括大脑在内的各种器官形成肿瘤。神经系统表现，例如癫痫，智力障碍和自闭症，通常是TSC最残疾的症状。理解TSC的分子发病机理的进展已导致TSC中肿瘤的新疗法，尤其是雷帕霉素复合物1（MTORC1）途径的哺乳动物靶标的抑制剂。然而，TSC中癫痫和认知障碍的病理生理学仍然知之甚少，对这些残疾神经系统症状的治疗仍然有限。在该赠款的先前资金期间，我们利用小鼠模型研究了TSC中癫痫发生的机制（例如TSC1GFAPCKO小鼠）。我们确定了有助于癫痫生成的神经元和神经元中的许多细胞和分子异常，例如星形胶质细胞增殖，神经胶质谷氨酸和钾缓冲，神经元死亡，神经元死亡以及MTORC1的失调。最值得注意的是，我们提供了证据，表明MTORC1抑制作用在预防TSC小鼠模型以及其他获得的（非基因）癫痫模型中的癫痫和相关病理异常方面具有抗癫痫作用作用。在此授予续签中，我们建议通过更具体地确定非神经细胞类型和先天免疫型在有助于TSC的神经系统型中的贡献来扩展我们的先前工作。我们的一般假设是，非神经元细胞，尤其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，在癫痫病和TSC的其他神经系统表现中起关键作用。该建议是专注于非神经细胞和先天免疫型在TSC的神经型表型中的新作用的创新性。该提案在测试新机械靶向的疗法方面还具有强大的临床意义和影响，这可能不仅有助于TSC的神经系统表现，而且有可能其他神经系统疾病。