[R21] Mechanistic Dissection of SRRM2-Mediated RNA Splicing and Subnuclear RNA Organization in Human Neurons

Ente: National Institute of Mental Health

Scadenza: 2028-08-13

Importo max: 462.000 EUR

Paese: US

Descrizione

PROJECT SUMMARY Schizophrenia is a severe neuropsychiatric disorder with high heritability, yet the molecular mechanisms linking genetic risk to neuronal dysfunction remain poorly understood. Emerging evidence points to post- transcriptional RNA regulation, such as RNA-binding proteins like Serine/Arginine Repetitive Matrix protein 2 (SRRM2), as a critical contributor to the disease. SRRM2 is a nuclear speckle-associated splicing regulator that has been implicated in schizophrenia risk through both common and rare variant studies. However, its functional role in human neurons remains largely unexplored. This project has two main aims. The first aim is to develop a novel spatial transcriptomics platform, Spatial RNA–Protein Interactome MERFISH (SPRIM), to visualize endogenous RNA–protein interactions at subcellular resolution. SPRIM integrates antibody-guided localization, in situ tagmentation, and multiplexed RNA detection to map RNA-binding protein targets in intact cells. The second aim is to investigate the roles of SRRM2 in engineered human induced neurons. Using adeno associated based gene editing, spatial imaging, and electrophysiology, we will assess how SRRM2 heterozygous loss affects RNA splicing, transcript localization, and neuronal electrophysiological properties. This exploratory project is well aligned with the NIH R21 funding mechanism, which supports innovative research. By developing a novel spatial omic platform and applying it to dissect SRRM2 function in genetically engineered human neurons, we aim to uncover foundational principles of RNA-binding protein mediated RNA regulation in brain development and psychiatric disease. Istituzione: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI PI: Cheen Euong Ang Progetto: 1R21MH144609-01

Settori: National Institute of Mental Health

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