Evaluation of the endocannabinoid system in isogenic neural models of neurodevelopmental disorders associated with sleep alterations

• Grant number: 24/13810-5
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: October 01, 2024
• End date: January 31, 2028
• Field of knowledge: Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
• Principal Investigator: Mariana Moysés Oliveira
• Grantee: Bruna Pereira Marquezini
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 21/09089-0 - High throughput genomic edition to investigate neurodevelopmental disorders using isogenic cellular models, AP.JP

Abstract

Neurodevelopmental disorders (NDDs) are complex conditions that encompass various neurological diseases, such as autism spectrum disorder, rare genetic syndromes, and epileptic encephalopathies (EEs). The genetic basis of syndromes associated with NDDs includes rare de novo genetic variants, both loss-of-function and gain-of-function, in evolutionarily conserved genes. These genetic variations constitute the most well-known risk factors associated with NDDs. Alterations in circadian rhythm are often associated with rare genetic syndromes related to NDDs. The GRIN2A gene encodes the GluN2A protein, a subunit of the glutamate receptor, and rare mutations in this gene are associated with EEs. It is known that about 30% of patients with EE are refractory, meaning they are resistant to drug treatment. The endocannabinoid system (ECS) is one of the main axes of the central nervous system and modulates both excitatory and inhibitory synaptic activity. Therefore, we will evaluate the presence of alterations in the endocannabinoid system among the functional convergences in mutational mechanisms associated with NDDs, using pathogenic variants in GRIN2A as an experimental model. We will apply genomic editing methodologies in human induced pluripotent stem cell (hiPSC) lines to introduce variants in GRIN2A observed in individuals with NDD/EE. This study will thus implement new technologies and novel neuronal models to assess whether the endocannabinoid system and circadian regulation are present in the convergence nodes of molecular signatures caused by NDD/EE in the edited isogenic neuronal lines.