Analysis of Tuberous Sclerosis Complex in Zebrafish

描述（由申请人提供）：多发性硬化症（TSC）是一种遗传性疾病，困扰着近50，000名美国人和全球至少100万人。TSC是一种破坏性的多器官疾病，导致良性肿瘤和严重的神经系统表现。癫痫是TSC的常见特征，至少90%的受影响个体产生从婴儿痉挛到复杂部分性癫痫发作的癫痫发作。虽然目前还没有治愈这种疾病的方法，但可以通过更深入地了解TSC癫痫的分子基础来开发改进的治疗方法。为了深入了解这种健康问题，已经通过使用吗啉代寡核苷酸敲低TSC基因功能开发了这种疾病的斑马鱼模型。在这个提议中，电生理记录和行为监测将被用来检查TSC缺陷的吗啡类药物的超兴奋性。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，将测试已知影响TSC信号传导途径的药理学药剂的治疗功效。这一建议可能会提供线索的原因癫痫TSC和确定生化治疗这种疾病的目标。

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.