Transcriptional Regulation Assessed in Neuronal Subtypes in three major interrelated Psychiatric disorders

Descrizione del progetto

Modelli di organoidi per i disturbi psichiatrici

La schizofrenia, il disturbo bipolare e il disturbo depressivo maggiore sono patologie psichiatriche interconnesse che condividono aspetti neurobiologici; ciononostante, i loro meccanismi di fondo sono tuttora poco conosciuti. I modelli di test esistenti presentano limitazioni significative, il che mette in evidenza la necessità di sviluppare nuovi approcci. Il progetto TRANS-PSYCH, finanziato dal CER, si prefigge di sviluppare modelli di organoidi per questi disturbi psichiatrici puntando su fattori di trascrizione a monte critici per la differenziazione dei tipi di cellule e la formazione di reti neuronali, secondo un’ipotesi di partenza in base alla quale questi fattori di trascrizione potrebbero fungere da bersaglio per modellare tali disturbi negli organoidi cerebrali. Il progetto sfrutterà la profilazione multi-omica su una collezione di alta qualità di tessuto cerebrale umano psichiatrico allo scopo di identificare i fattori di trascrizione chiave, che verranno poi indirizzati in sistemi di organoidi cerebrali per creare modelli neurobiologici di disturbi psichiatrici.

Obiettivo

Schizophrenia (SCZ), bipolar disorder (BP), and Major Depressive Disorder (MD) are three major psychiatric disorders that affect mood, thinking, and behavior. These disorders are strongly genetically intercorrelated, and exhibit pronounced clinical overlap, suggesting that they are different manifestations of a shared underlying neurobiology, along a spectrum. However, the neurobiological mechanisms and pathophysiology of these disorders are still poorly understood, limiting effective drug discovery. There is an urgent need for new models for drug testing, as animal models have major limitations, and current psychiatric organoids systems are dependent on patient derived stem cells, in which technical, genetic and biological diversity confound the interpretation, and obscure the underlying neuropathology. The major challenge of this ERC proposal is to develop organoid models for psychiatric disorders by targeting upstream transcription factors. Transcription factors are key molecules that drive cell type differentiation including neuronal network formation. Hence, the central hypothesis of this ERC proposal is that neuronal subtype associated transcription factors can function as targets to model these disorders using brain organoids. However, the neuronal transcriptional regulators that mediate these disorders are currently unknown, and difficult to identify. Novel genomics technologies allow for an unbiased characterization of the brain in order to detect cell types and genes that are dysregulated in disease, and can be used to identify putative upstream transcription factors. Here, I propose a selection of multi-omics profiling - strategies to a unique collection of high quality psychiatric human brain tissue aimed at reliably identifying key upstream transcription factors. We will subsequently target those transcription factors in brain organoid systems to establish neurobiological models of these disorders.