Control of Seizure and Migraine Susceptibility by GPR37L1

项目摘要 癫痫和偏头痛长期以来被认为在某些家庭中有联系，但遗传基础 对这个科摩罗的了解并不多。我们和其他人最近发现了人类遗传 研究表明，GPR37L1的变异是癫痫和偏头痛风险的主要因素，特别是在 癫痫和偏头痛并存GPR37L1主要在星形胶质细胞中表达，因此 对这种受体的研究可能会导致更全面的了解星形胶质细胞功能障碍如何有助于 癫痫和偏头痛。这个项目的目标是阐明细胞和机制的基础， GPR37L1调节癫痫发作和偏头痛易感性。我们将评估运输和信号性质 疾病相关的GPR37L1变异的星形胶质细胞，并解决了为什么GPR37L1 信号传导似乎依赖于星形胶质细胞的环境。另外，我们会研究 基因敲入小鼠携带致病性人类变异的脆弱性，并探讨星形胶质细胞 人皮质类器官的发育受GPR37L1的致病性变体的影响。此外，我们将 评估缺乏Gpr37L1或表达致病性Gpr37L1变体的小鼠的偏头痛相关表型 并评估这些突变小鼠大脑皮层回路兴奋性的变化， 和癫痫发作表型。这些研究将为GPR37L1的基础生物学提供新的见解。 也为开发新的GPR37L1靶向治疗药物铺平了道路， 癫痫、偏头痛等疾病。

Project Summary Epilepsy and migraine have long been recognized as being linked in certain families, but the genetic basis of this comorbidity in not well understood. We and others have recently found evidence in human genetic studies that variation in GPR37L1 is a major contributor to epilepsy and migraine risk, especially in cases where epilepsy and migraine are comorbid. GPR37L1 is expressed predominantly in astrocytes, and thus studies on this receptor may lead to more general insights into how astrocyte dysfunction contributes to epilepsy and migraine. The goal of this project is to elucidate the cellular and mechanistic basis by which GPR37L1 regulates seizure and migraine susceptibility. We will assess the trafficking and signaling properties of disease-associated GPR37L1 variants in astrocytes and also address the mystery of why GPR37L1 signaling appears to be dependent on the astrocytic context. Furthermore, we will study the seizure vulnerability of knock-in mice harboring pathogenic human variants and also explore how astrocyte development in human cortical organoids is affected by pathogenic variants of GPR37L1. Additionally, we will assess mice lacking Gpr37L1 or expressing pathogenic Gpr37L1 variants for migraine-relevant phenotypes and evaluate these mutant mice for changes in cortical circuit excitability that might inform both the migraine and seizure phenotypes. These studies will provide novel insights into the fundamental biology of GPR37L1 and also pave the way for the development of novel GPR37L1-targeted therapeutics for the treatment of epilepsy, migraine and other diseases.