The role of NPRL2 loss in focal cortical dysplasia

项目摘要 大脑发育畸形是儿童神经功能障碍的常见原因。最多的 这些神经发育障碍中常见的是一大群皮质发育畸形。 (MCD)以大脑皮层结构破坏为特征(例如，细胞大小增大，改变 层压)。已在PI3K-AKT3-mTOR(MTOR)调控基因中发现了体细胞突变 这些MCD患者脑组织中的通路统称为mTORopathies。局灶性皮质 发育不良是一种特别具有挑战性的mTOR病，因为存在高度致痫的病变 通常对药物有抵抗力和/或难以切除的皮质。最常见的遗传变异 导致FCD的基因编码形成GATOR1复合体的蛋白质亚单位：DEPDC5，NPRL2， 和NPRL3--mTOR信号的负调控因子。许多研究已经将DEPDC5和NPRL3的变异联系在一起 与mTOR通路过度激活、MCD和癫痫发作有关，但很少有功能验证或建模的研究 目前，NPRL2和mTOR抑制剂的变种不用于治疗这些患者的癫痫。这个项目 目的研究Nprl2在体内外的丢失效应，并鉴定mTOR依赖的mTOR 由于Nprl2 KO而发生的转录转录变化。这项提议的结果将提供一个深刻的 对NPRL2变异相关表型的功能和转录水平的了解，为临床前提供 支持在受影响的个体中使用mTOR抑制剂，并确定下游的新治疗靶点 可能在未来提供精确治疗选择的mTOR。

Project Summary Malformations of brain development are a common cause of neurological disorders in children. The most common of these neurodevelopmental disorders is the large group of malformations of cortical development (MCD) characterized by disruption of the structure of the cerebral cortex (e.g., enhanced cell size, altered lamination). Somatic mutations have been identified in regulatory genes of the PI3K-AKT3-mTOR (mTOR) pathway in the brain tissue of patients with these MCD collectively termed ‘mTORopathies.’ Focal cortical dysplasia is a particularly challenging mTORopathy due to the presence of highly epileptogenic lesions within the cortex that are often resistant to medication and/or difficult to resect. The most common genetic variants causing FCD are found in genes that encode protein subunits forming the GATOR1 complex: DEPDC5, NPRL2, and NPRL3- a negative regulator of mTOR signaling. Many studies have linked variants in DEPDC5 and NPRL3 to mTOR pathway hyperactivation, MCD, and seizures, but there few studies functionally validating or modeling variants in NPRL2 and, currently, mTOR inhibitors are not used to treat epilepsy in these patients. This project seeks to investigate the effects of Nprl2 loss in vitro and in vivo and to identify the mTOR-dependent transcriptomic changes that occur as a result of Nprl2 KO. The results of this proposal stand to provide a deep functional and transcriptomic understanding of NPRL2 variant associated phenotypes, provide pre-clinical support for the use of mTOR inhibitors in effected individuals, and identify novel therapeutic targets downstream of mTOR that may provide precision therapy options in the future.