Exploring Novel Epilepsy Pathways

项目摘要/摘要 癫痫是一种常见的致残性疾病，目前的治疗方法仍然不足。癫痫是 已知有很大的遗传贡献，但总体上一小部分癫痫是由已知的 基因和机制。因此，迫切需要确定构成其基础的分子和途径 癫痫的病理生理学和寻找新的治疗策略。专注于通向 不同物种和模型系统中与癫痫相关的表型可能有助于加快发现过程。 最近，我们发现棘突基因的突变可以导致多种物种的癫痫发作，范围从 飞向人类。该系统可为开发更安全、更有效的药物提供依据 治疗癫痫的药物疗法。我们的初步发现使我们得出这样的假设，即基因突变 刺痛通路与癫痫有关，刺痛调节剂可用于治疗 癫痫或癫痫发作。此R01应用程序的目标是识别与刺痛相关的分子 信号传递和确定棘突通路调节试剂是否能减轻我们多发性癫痫发作 模型系统。这里提出的研究应该既能加深我们对白纹伊蚊生物学的理解 刺痛及其与癫痫的联系，并导致新的治疗方式。我们的具体目标是：1) 测试棘路分子作为抗癫痫药物靶点；2)测试Wnt5a及相关分子 作为多刺突变小鼠的抗癫痫药物。这些实验应该能让我们更深入地了解 刺痛信号，它是如何发生的，以及刺痛调节试剂是否提供新的癫痫治疗。

Project Summary/Abstract Epilepsy is a common and disabling disease for which current treatments remain inadequate. Epilepsy is known to have a major genetic contribution, but a small proportion of epilepsy overall is explained by known genes and mechanisms. Thus, there is a critical need to identify the molecules and pathways that underlie epilepsy pathophysiology and to find novel therapeutic strategies. Focusing on pathways which lead to epilepsy-related phenotypes in diverse species and model systems may help accelerate the discovery process. Recently we found mutations in the Prickle genes can contribute to seizures in multiple species ranging from flies to humans. This system can provide a basis for the development of safer and more effective drug regimens for treating epilepsy. Our preliminary findings led us to the hypothesis that mutations in the PRICKLE pathway are associated with epilepsy and that Prickle-modulating reagents can be used to treat epilepsy or seizures. The objective of this R01 application is to identify the molecules involved in Prickle signaling and to determine whether Prickle pathway-modulating reagents alleviate seizures in our multiple model systems. The studies proposed here should both further our understanding of the biology of the Prickles and their connection to epilepsy, and lead to new therapeutic modalities. Our specific aims are: to 1) Test Prickle-pathway molecules as anti-epilepsy drug targets and 2) Test Wnt5a and related molecules as anti-epileptics in Prickle mutant mice. These experiments should provide insight into the biology of Prickle signaling, how it and whether Prickle-modulating reagents offer new epilepsy treatments.