Control of Seizure and Migraine Susceptibility by GPR37L1

项目摘要 癫痫和偏头痛长期以来一直被认为在某些家族中有关联，但遗传基础 这种合并症的原因还不是很清楚。我们和其他人最近在人类基因中发现了证据 研究表明，GPR37L1的变异是癫痫和偏头痛风险的主要贡献者，尤其是在 癫痫和偏头痛并存的地方。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对星形胶质细胞功能障碍如何导致 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。我们将评估贩运和信号特性 星形胶质细胞中与疾病相关的GPR37L1变异体，并解决了为什么GPR37L1 信号似乎依赖于星形细胞的背景。此外，我们将研究扣押 携带致病人类变异基因的敲入小鼠的脆弱性，并探索星形胶质细胞如何 人类皮质类器官的发育受到GPR37L1致病变异体的影响。此外，我们还将 评估缺乏GPR37L1或表达致病GPR37L1变异的小鼠偏头痛相关表型 并评估这些突变小鼠皮层回路兴奋性的变化，这可能会通知偏头痛 和癫痫的表型。这些研究将为GPR37L1的基础生物学提供新的见解 也为GPR37L1靶向治疗白血病的新型药物的开发铺平了道路 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.