Understanding GRIN2B-Related Neurodevelopmental Disorder from a human brain organoid perspective. Use of flavonoids as a therapeutic approach.

FIORE L; COLETTIS, NATALIA

Mesa redonda; GRIN genes Roundtable summary; 2020

Cure Grin

ESC-derived brain organoids have shed new light on brain development and have proved to be a reliable tool for modeling human brain diseases. In order to study the role of GRIN2B in human brain development under both normal and GRIN2B-related pathological conditions, hESC with multiple GRIN2B genetic variants will be obtained through CRISPR/CAS9 gene editing. These generated genetic variants will be analyzed at three main levels: 1) transcriptome 2) cellular organization and morphogenesis and 3) synapses morphology. The expression pattern and functional analysis of GRIN2B during brain morphogenesis will be investigated by using immunofluorescence microscopy and RNA-seq analysis. Moreover, the organoid in vitro approach allows the functional analysis in response to external inputs, e.g. pharmaceutical intervention. Flavonoids exert a wide range of actions on the brain, including modulation of cellular pathways related to GRIN2B. Novel synthetic and natural flavonoids from our laboratory bank will be tested on brain organoids carrying human GRIN2B genetic variants to find therapeutic tools for patients with GRIN2B disorders. The proposed experimental design allows us to test a combination of GRIN2B variants with different flavonoids simultaneously. This project will further our understanding of GRIN2B pathologies and will provide novel therapeutic techniques to improve the quality of lives of patients with GRIN2B disorders.