The role of NPRL2 loss in focal cortical dysplasia

NPRL2 缺失在局灶性皮质发育不良中的作用

基本信息

批准号：
10634155
负责人：
Philip Henry Iffland
金额：
$ 38.63万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634155
关键词：
AKT3 gene Address Amino Acids Animals Architecture Binding Biological Assay CRISPR/Cas technology Cell Aggregation Cell Size Cells Cellular Morphology Cerebral cortex Childhood Neurological Disorder Complex Cortical Dysplasia Cortical Malformation Defect Dendrites Dependence Development Developmental Delay Disorders Disease Dissociation EIF4EBP1 gene Electroencephalography Electroporation Ephrin-A5 Epilepsy FRAP1 gene Fluorescence Future Genes Growth Harvest Image Image Cytometry Immunochemistry In Vitro Individual Intellectual functioning disability Intractable Epilepsy Knowledge Lesion Link Lysosomes Manuals Measurement Medical Modeling Monitor Morphology Mus Neurodevelopmental Disorder Neurons Operative Surgical Procedures PIK3CG gene Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphorylation Plasmids Precision therapeutics Process Protein Subunits Proteins Proto-Oncogene Proteins c-akt Regulator Genes Resected Resistance Role STAT3 gene Seizures Signal Transduction Sirolimus Somatic Mutation Specimen Starvation Structure TSC2 gene Testing Variant Western Blotting autism spectrum disorder brain malformation brain tissue cell cortex cell type differential expression experimental study genetic variant immunocytochemistry in utero in vivo mTOR Inhibitor mTORopathies mouse model neuronal cell body new therapeutic target novel pharmacologic pre-clinical preclinical study pup response single nucleus RNA-sequencing transcriptome transcriptomics

项目摘要

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.

项目概要大脑发育畸形是儿童神经系统疾病的常见原因。这些神经发育障碍的共同点是一大群皮质发育畸形 (MCD) 的特征是大脑皮层结构的破坏（例如，细胞尺寸增大、细胞尺寸改变、层压）已在 PI3K-AKT3-mTOR (mTOR) 调控基因中发现体细胞突变。这些 MCD 患者脑组织中的通路统称为“mTORopathies”。发育不良是一种特别具有挑战性的 mTOR 病，因为其内部存在高度致癫痫性病变。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。 FCD 存在于编码形成 GATOR1 复合体的蛋白质亚基的基因中：DEPDC5、NPRL2、 NPRL3（mTOR 信号转导的负调节因子）许多研究已将 DEPDC5 和 NPRL3 的变异联系起来。 mTOR 通路过度激活、MCD 和癫痫发作，但很少有研究进行功能验证或建模 NPRL2 变体和 mTOR 抑制剂目前不用于治疗这些患者的癫痫。旨在研究 Nprl2 缺失在体外和体内的影响，并确定 mTOR 依赖性 Nprl2 KO 导致的转录组变化该提案的结果提供了深入的研究。对 NPRL2 变异相关表型的功能和转录组理解，提供临床前支持在受影响的个体中使用 mTOR 抑制剂，并确定下游治疗新靶点 mTOR 可能会在未来提供精准治疗选择。