Characterization of the Hypothalamus in Autism Spectrum Disorder: A Multi-Omic Approach Using Animal Models and Organoids

• Grant number: 24/19422-7
• Support Opportunities: Generation Project Research Grant
• Start date: February 01, 2026
• End date: January 31, 2031
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: João Victor Silva Nani
• Grantee: João Victor Silva Nani
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Alysson Renato Muotri ; Andre de Souza Mecawi ; David Murphy ; Elisa Rennó Donnard Moreira
• Associated scholarship(s): 26/02908-0 - Standardization of Single-Cell Level Proteome/Phosphoproteome Data Deconvolution Pipelines, BP.TT; 26/00477-1 - Characterization of the Hypothalamus in Autism Spectrum Disorder: A Multi-Omic Approach Using Animal Models and Organoids, BP.GR

Abstract

Autism Spectrum Disorder (ASD) is a neuropsychiatric condition characterized by a wide range of symptoms that affect social interaction, communication, and behavior, impacting approximately 2 million people in Brazil. While most research focuses on alterations in cortical areas of the brain, this project aims to characterize changes in hypothalamic nuclei, responsible for the synthesis of neuropeptides fundamental in regulating social behaviors, such as oxytocin (OXT) and vasopressin (AVP). Polymorphisms in the genes of OXT and AVP receptors have been associated with social deficits in ASD, and therapies with exogenous OXT show therapeutic potential. With the advancement of single-cell and single-nucleus sequencing technologies, such as scRNA-seq and ATAC-seq, and the incorporation of proteomic and phosphoproteomic analyses, new opportunities arise to investigate modifications in the transcriptome, chromatin structure, and proteomic dynamics associated with ASD. This project proposes a multi-omic analysis using these techniques, focusing on the hypothalamus of animal models of ASD and on human hypothalamic organoids derived from pluripotent stem cells, allowing the exploration of molecular and epigenetic signatures in various cell types and at different developmental stages. Furthermore, our objective is to build a comparative multi-species atlas, integrating single-cell transcriptome data from humans, animal models, and hypothalamic organoids. Bioinformatic analyses and multi-omic and multi-species integration will consolidate a solid knowledge base, enabling a broader and more precise understanding of the molecular and functional networks of ASD. This innovative approach will fill a critical gap in understanding the condition and pave the way for the identification of new therapeutic targets, promoting significant advances in the treatment of ASD. (AU)