Identification of molecular profiles in the rare genetic syndrome associated with SYNGAP1 in isogenic neuronal models

• Grant number: 23/09760-0
• Support Opportunities: Scholarships in Brazil - Support Program for Fixating Young Doctors
• Start date: August 01, 2023
• End date: June 30, 2025
• Field of knowledge: Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
• Agreement: CNPq
• Principal Investigator: Mariana Moysés Oliveira
• Grantee: Amanda Cristina Mosini
• Host Institution: Associação Fundo de Incentivo à Pesquisa (AFIP). São Paulo , SP, Brazil
• Associated research grant: 23/01515-6 - Identification of molecular profiles in the Rare Genetic Syndrome associated with SYNGAP1 in isogenic neuronal models, AP.R

Abstract

Epileptic encephalopathies (EEs) are epileptic conditions characterized by epileptiform abnormalities associated with progressive brain dysfunction. One of the genes related to EEs is the SYNGAP1 gene, which is related to the synaptic activity of excitatory neurons, so that haploinsufficiency of this gene impairs neuronal development. In this proposal, we will establish a large-scale CRISPR-based genomic engineering platform that allows simultaneous genome edits. We will apply this genome editing platform to human induced pluripotent stem cell (hiPSC) lineages aiming the introduction of variants in SYNGAP1. These cellular models will be differentiated into neural stem cells and cortical glutamatergic neurons in order to interrogate the molecular consequences of these genetic perturbations. Our aims are: Aim1: To determine the molecular impact (global transcriptional and neuroinflammatory profile) of genetic variations introduced by CRISPR by investigating hiPSC-derived neuronal models. Aim 2: To evaluate physiological (sleep pattern), molecular (inflammatory profile) and cognitive (social interaction and learning) aspects of patients with variants in SYNGAP1. Aim 3: To correlate clinical assessments performed in patients with assessments performed in in vitro neuronal models containing variants, aiming at Precision Medicine approaches. This study will therefore implement new technologies, generate neuronal models, and integrate datasets to identify convergence points in molecular signatures caused by EE, which in future studies may constitute targets for pharmacological manipulations.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MOSINI, AMANDA CRISTINA; MOYSES-OLIVEIRA, MARIANA; DE ARAUJO, JESSICA NAYARA GOES; GUERREIRO, PEDRO; CUNHA, LAIS; ZAMARIOLLI, MALU; XAVIER, SANDRA DORIA; BALBUENO, BIANCA; DE MELLO, CLAUDIA BERLIM; MOREIRA, GUSTAVO ANTONIO; et al. Sleep complaints in individuals with SYNGAP1-associated syndrome. Sleep Medicine, v. 126, p. 8-pg., 2024-12-28. (21/09089-0, 20/13467-8, 24/05023-3, 23/14935-3, 23/09760-0)

MOSINI, AMANDA CRISTINA; ADAMI, LUANA NAYARA GALLEGO; VALLIM, JULIA RIBEIRO DA SILVA; MOYSES-OLIVEIRA, MARIANA; POYARES, DALVA; ANDERSEN, MONICA L.; TUFIK, SERGIO. Leptin moderates the relationship between sleep quality and memory function: A population-based study. Sleep Medicine, v. 117, p. 6-pg., 2024-03-26. (23/09760-0, 21/09089-0, 20/13467-8)