结节性硬化症（TSC）是一种由Tsc1或（和）Tsc2基因突变而导致的常染色体显性遗传病，其中枢神经系统的临床表现主要为癫痫发作、认知障碍和精神活动异常。目前认为，由锥体神经元迁移及形态异常而导致的皮层发育畸形是TSC相关中枢症状的病理基础，但其具体分子调控机制尚不清楚。在前期研究中，我们首次揭示了FLNA蛋白对神经元树突发育的调控功能，其表达的异常增高是Tsc1-/-神经元树突过度发育的重要原因，且表现为雷帕霉素耐药。结合前期研究及相关背景，本项目拟探讨（1）FLNA对皮层发育的调控作用；（2）抑制FLNA过表达能否阻止TSC相关的皮层发育畸形和癫痫发作；（3）靶向FLNA的小分子抑制剂PTI-125对TSC疾病的治疗效果。在完善对TSC发病机制研究的基础上，本项目将为临床治疗提供新的理论依据，为药物研发提供新的靶点，实现基础到临床的转化。

Tuberous Sclerosis Complex (TSC), an autosomal dominant disorder, is caused by mutations in Tsc1 or (and) Tsc2 gene. Seizures, cognitive and neuropsychiatric disabilities are TSC’s most common neurological symptoms resulting from anomalies in cortical development. Neuronal dysmorphogenesis and migration deficits are considered to be the cellular abnormalities of cortical malformation, however, the precise molecular mechanisms remains unknown. Our previous studies identified FLNA as a novel regulator of neuronal dendritic development, and aberrant increased FLNA in Tsc1-/- neurons is responsible for complex dendritic arborization with a rapamycin-insensitive pattern. In light of our published (or preliminary) data and recent studies, this proposal aims to explore (1) FLNA as a contributor to regulating cortical development; (2) whether decreasing FLNA levels during development prevents TSC-associated cortical malformations and seizure activity; (3) the efficiency of PTI-125 (an inhibitor targeting FLNA) treatments at preventing TSC-associated cortical malformations and seizures. Our studies will provide a new theoretical framework for clinical treatment and new targets for drug development based on an in-depth investigation of the mechanisms involved in TSC, realizing the translation from basic research to clinical practice.