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:
- 金额:$ 38.63万
- 依托单位:
- 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:
- 关键词:AKT3 geneAddressAmino AcidsAnimalsArchitectureBindingBiological AssayCRISPR/Cas technologyCell AggregationCell SizeCellsCellular MorphologyCerebral cortexChildhood Neurological DisorderComplexCortical DysplasiaCortical MalformationDefectDendritesDependenceDevelopmentDevelopmental Delay DisordersDiseaseDissociationEIF4EBP1 geneElectroencephalographyElectroporationEphrin-A5EpilepsyFRAP1 geneFluorescenceFutureGenesGrowthHarvestImageImage CytometryImmunochemistryIn VitroIndividualIntellectual functioning disabilityIntractable EpilepsyKnowledgeLesionLinkLysosomesManualsMeasurementMedicalModelingMonitorMorphologyMusNeurodevelopmental DisorderNeuronsOperative Surgical ProceduresPIK3CG genePathway interactionsPatientsPharmaceutical PreparationsPhenotypePhosphorylationPlasmidsPrecision therapeuticsProcessProtein SubunitsProteinsProto-Oncogene Proteins c-aktRegulator GenesResectedResistanceRoleSTAT3 geneSeizuresSignal TransductionSirolimusSomatic MutationSpecimenStarvationStructureTSC2 geneTestingVariantWestern Blottingautism spectrum disorderbrain malformationbrain tissuecell cortexcell typedifferential expressionexperimental studygenetic variantimmunocytochemistryin uteroin vivomTOR InhibitormTORopathiesmouse modelneuronal cell bodynew therapeutic targetnovelpharmacologicpre-clinicalpreclinical studypupresponsesingle nucleus RNA-sequencingtranscriptometranscriptomics
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.
项目摘要
脑发育畸形是儿童神经系统疾病的常见原因。最
这些神经发育障碍中常见的是大量的皮质发育畸形
(MCD)其特征是大脑皮质结构的破坏(例如,细胞大小增大,改变
层压)。已经在PI 3 K-AKT 3-mTOR(mTOR)的调节基因中鉴定了体细胞突变。
这些MCD患者的脑组织中存在一种称为“mTORopathies”的信号通路。局灶性皮质
发育不良是一种特别具有挑战性的mTOR病变,由于存在高度致痫性病变,
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
引起FCD的基因编码形成GATOR 1复合物的蛋白亚基:DEPDC 5,NPRL 2,
和NPRL 3-mTOR信号传导的负调节剂。许多研究将DEPDC 5和NPRL 3的变异联系起来
mTOR通路过度激活,MCD和癫痫发作,但很少有功能验证或建模的研究
NPRL 2的变体和目前的mTOR抑制剂不用于治疗这些患者的癫痫。这个项目
试图研究体外和体内Npr 12损失的影响,并鉴定mTOR依赖性的
Nprl 2 KO导致的转录组学变化。这项提案的结果将提供一个深刻的
对NPRL 2变体相关表型的功能和转录组学理解,提供临床前
支持在受影响的个体中使用mTOR抑制剂,并鉴定下游新的治疗靶点
mTOR,这可能会在未来提供精确的治疗选择。
项目成果
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