Analysis of Tuberous Sclerosis Complex in Zebrafish

描述(申请人提供)：结节性硬化症(TSC)是一种遗传性疾病，困扰着近5万美国人和全球至少100万人。TSC是一种破坏性的多器官疾病，会导致良性肿瘤和严重的神经系统症状。癫痫是TSC的常见特征，至少90%的患者会出现从婴儿痉挛到复杂的部分性发作的癫痫发作。虽然目前还没有治愈这种疾病的方法，但通过更彻底地了解TSC癫痫的分子基础，可能会开发出改进的治疗方法。为了深入了解这一健康问题，通过使用吗啉寡核苷酸敲除TSC基因功能，建立了这种疾病的斑马鱼模型。在这项建议中，将使用电生理记录和行为监测来检测TSC缺乏的变形体中的过度兴奋。将对大脑形态进行全面分析，以揭示TSC缺乏对发育的影响。最后，已知影响TSC信号通路的药理制剂将接受治疗效果测试。这一建议可能为TSC癫痫的病因提供线索，并确定治疗该疾病的生化指标。

DESCRIPTION (provided by applicant): Tuberous sclerosis complex (TSC) is a genetic disease afflicting nearly 50,000 Americans and at least one million individuals worldwide. TSC is a devastating multi-organ disease that results in benign tumors and severe neurological manifestations. Epilepsy is a common feature of TSC, with at least 90% of affected individuals generating seizures ranging from infantile spasms to complex partial seizures. While there currently is no cure for this disease, improved therapies may be developed from a more thorough understanding of the molecular basis of epilepsy in TSC. To gain insight into this health problem, a zebrafish model of this disease has been developed by knocking-down TSC gene function using morpholino oligonucleotides. In this proposal, electrophysiological recordings and behavioral monitoring will be used to examine the hyperexcitable in TSC-deficient morphants. A comprehensive analysis of brain morphology will be performed to uncover the developmental effects of TSC deficiency. Finally, pharmacological agents, known to affect the TSC signaling pathway, will be tested for therapeutic efficacy. This proposal may provide clues into the causes of epilepsy in TSC and identify biochemical targets for treating this disease.