Control of Seizure and Migraine Susceptibility by GPR37L1

GPR37L1 控制癫痫和偏头痛易感性

• 批准号: 10279634
• 负责人: Randy A. Hall
• 金额: $ 50.17万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10279634
• 关键词: Acute; Address; Affect; Astrocytes; Binding; Biology; Brain; Data Set; Development; Disease; Epilepsy; Exhibits; Family; Follow-Up Studies; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic; Genetic Variation; Genetic study; Goals; Human; Human Biology; Human Genetics; Hyperalgesia; Knock-in Mouse; Lead; Light; Link; Migraine; Migraine Variants; Modeling; Mus; Mutant Strains Mice; Nitroglycerin; Organoids; Pathogenicity; Pathology; Patients; Pharmacology; Phenotype; Physiological; Physiology; Play; Population; Predisposition; Process; Progressive Myoclonic Epilepsies; Property; Proteins; Proteomics; Risk; Rodent Model; Role; Scaffolding Protein; Seizures; Signal Transduction; Spreading Cortical Depression; Testing; Transcript; Variant; Wild Type Mouse; Work; base; brain tissue; comorbidity; exome; experimental study; family genetics; genetic association; human disease; induced pluripotent stem cell; insight; novel; novel therapeutics; receptor; receptor function; segregation; targeted treatment; trafficking; transcriptome sequencing

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.

项目概要 长期以来，人们一直认为癫痫和偏头痛在某些家族中存在关联，但遗传基础 对这种合并症的了解还不是很清楚。我们和其他人最近发现了人类遗传的证据 研究表明 GPR37L1 的变异是癫痫和偏头痛风险的主要原因，尤其是在某些情况下 癫痫和偏头痛同时存在的地方。 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的更普遍的了解 癫痫和偏头痛。该项目的目标是阐明细胞和机制基础 GPR37L1 调节癫痫发作和偏头痛的易感性。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 变异的研究，并解决了 GPR37L1 为何存在的谜团 信号传导似乎依赖于星形细胞环境。此外，我们还将研究癫痫发作 携带人类致病变异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 致病变异的影响。此外，我们将 评估缺乏 Gpr37L1 或表达致病性 Gpr37L1 变异的小鼠的偏头痛相关表型 并评估这些突变小鼠皮质回路兴奋性的变化，这可能会导致偏头痛 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 并为开发新的 GPR37L1 靶向治疗药物铺平道路 癫痫、偏头痛和其他疾病。