MECHANISMS OF BRAIN DYSFUNCTION IN TUBEROUS SCLEROSIS

 描述（由申请人提供）：脑硬化综合征（TSC）是一种遗传性疾病，其特征是在包括脑在内的各种器官中形成肿瘤。神经系统表现，如癫痫，智力障碍和自闭症，通常是TSC最致残的症状。对TSC分子发病机制的理解的进展导致了TSC肿瘤的新疗法，特别是雷帕霉素复合物1（mTORC 1）通路的哺乳动物靶点的抑制剂。然而，TSC中癫痫和认知障碍的病理生理学仍然知之甚少，并且这些致残性神经系统症状的治疗仍然有限。在该资助的先前资助期间，我们利用小鼠模型来研究TSC中癫痫发生的机制（例如Tsc1GFAPCKO小鼠）。我们确定了一些神经胶质细胞和神经元的细胞和分子异常，有助于癫痫发生，如星形胶质细胞增殖，受损的神经胶质细胞谷氨酸和钾缓冲，神经元死亡，mTORC 1的失调。最值得注意的是，我们提供的证据表明，mTORC1抑制在预防TSC小鼠模型以及其他获得性（非遗传性）癫痫模型中的癫痫和相关病理异常方面具有抗癫痫作用。在这次资助更新中，我们建议通过更具体地确定非神经元细胞类型和先天免疫对TSC神经表型的贡献来扩展我们以前的工作。我们的一般假设是，非神经元细胞，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，在癫痫的病理生理学和TSC的其他神经学表现中发挥关键作用。该建议是创新的，重点是非神经元细胞和先天免疫在TSC的神经表型中的新作用。该提案在测试新的机械靶向疗法方面也具有很强的临床意义和影响，这不仅可能有益于TSC的神经学表现，而且可能有益于其他神经系统疾病。

 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.